Spontaneous Bacterial Peritonitis
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Background
Spontaneous bacterial peritonitis (SBP) is an acute bacterial infection of ascitic fluid. Generally, no source of the infecting agent is easily identifiable, but contamination of dialysate can cause the condition among those receiving peritoneal dialysis (PD).
Spontaneous bacterial peritonitis occurs in both children and adults and is a well-known and ominous complication in patients with cirrhosis.Of patients with cirrhosis who have spontaneous bacterial peritonitis, 70% are Child-Pugh class C. In these patients, the development of spontaneous bacterial peritonitis is associated with a poor long-term prognosis.
Once thought to occur only in those individuals with alcoholic cirrhosis, spontaneous bacterial peritonitis is now known to affect patients with cirrhosis from any cause. In addition, spontaneous bacterial peritonitis can occur as a complication of any disease state that produces the clinical syndrome of ascites, such as heart failure and Budd-Chiari syndrome. Children with nephrosis or systemic lupus erythematosus who have ascites have a high risk of developing spontaneous bacterial peritonitis.
Pathophysiology
The mechanism for bacterial inoculation of ascites has been the subject of much debate since Harold Conn first recognized the disorder in the 1960s. Enteric organisms have traditionally been isolated from more than 90% of infected ascites fluid in spontaneous bacterial peritonitis, suggesting that the GI tract is the source of bacterial contamination.
The preponderance of enteric organisms, in combination with the presence of endotoxin in ascitic fluid and blood, once favored the argument that spontaneous bacterial peritonitis was due to direct transmural migration of bacteria from an intestinal or hollow organ lumen, a phenomenon called bacterial translocation. However, experimental evidence suggests that direct transmural migration of microorganisms might not be the cause.
An alternative proposed mechanism for bacterial inoculation of ascites is hematogenous transmission in combination with an impaired immune system. Nonetheless, the exact mechanism of bacterial displacement from the GI tract into ascites fluid remains controversial.
A variety of factors contributes to peritoneal inflammation and bacterial growth in ascitic fluid. A key predisposing factor may be the intestinal bacterial overgrowth found in people with cirrhosis, mainly attributed to delayed intestinal transit time. Intestinal bacterial overgrowth, along with impaired phagocytic function, low serum and ascites complement levels, and decreased activity of the reticuloendothelial system, contributes to an increased number of microorganisms and decreased capacity to clear them from the bloodstream, resulting in their migration into and eventual proliferation within ascites fluid.
Interestingly, adults with spontaneous bacterial peritonitis typically have ascites, but most children with spontaneous bacterial peritonitis do not have ascites. The reason for and mechanism behind this is the source of ongoing investigation.
Etiology
Traditionally, three fourths of spontaneous bacterial peritonitis infections have been caused by aerobic gram-negative organisms (50% of these being Escherichia coli). The remainder has been due to aerobic gram-positive organisms (19% streptococcal species). E coli is displayed in the image below.
However, some data suggest that the percentage of gram-positive infections may be increasing.One study cites a 34.2% incidence of streptococci, ranking in second position after Enterobacteriaceae.Viridans group streptococci (VBS) accounted for 73.8% of these streptococcal isolates.
Anaerobic organisms are rare because of the high oxygen tension of ascitic fluid.
A single organism is noted in 92% of cases, and 8% of cases are polymicrobial.
Risk factors
Patients with cirrhosis who are in a decompensated state are at the highest risk of developing spontaneous bacterial peritonitis.Low complement levels are associated with the development of spontaneous bacterial peritonitis. Patients at greatest risk for spontaneous bacterial peritonitis have decreased hepatic synthetic function with associated low total protein level or prolonged prothrombin time (PT).
Patients with low protein levels in ascitic fluid (< 1 g/dL) have a 10-fold higher risk of developing spontaneous bacterial peritonitis than those with a protein level greater than 1 g/dL.
In a 2012 review by Siple et al,they show several case studies and cohorts of patients with cirrhosis and chronic liver disease who were on proton pump inhibitors (PPIs) for a prolonged duration who were at significantly increased risk for the development of spontaneous bacterial peritonitis. While prospective studies are needed on this subject, there appears to be a direct correlation between a lack of an acidic environment and portal hypertension to put these patients at increased risk for spontaneous bacterial peritonitis. Thus, in patients on long-term PPI therapy, the suspicion for infection should be heightened and the benefit of long-term PPI therapy should outweigh the risk for the development of spontaneous bacterial peritonitis.
Epidemiology
In patients with ascites, the frequency may be as high as 18%. This number has grown from 8% over the past 2 decades, most likely secondary to an increased awareness of spontaneous bacterial peritonitis and a lowered threshold to perform diagnostic paracentesis.
No race predilection is known for spontaneous bacterial peritonitis. In patients with ascites, both sexes are affected equally.
Although the etiology and incidence of hepatic failure differ between children and adults, in those individuals with ascites, the incidence of spontaneous bacterial peritonitis is roughly equal. Two peak ages for spontaneous bacterial peritonitis are characteristic in children: the first in the neonatal period and the second at age 5 years.
Prognosis
The mortality rate in patients with spontaneous bacterial peritonitis ranges from 40-70% in adult patients with cirrhosis. Rates are lower in children with nephrosis. Patients with concurrent renal insufficiency have been shown to be at a higher risk of mortality from spontaneous bacterial peritonitis than those without concurrent renal insufficiency. Mortality from spontaneous bacterial peritonitis may be decreasing among all subgroups of patients because of advances in its diagnosis and treatment.
History
A broad range of signs and symptoms are seen in spontaneous bacterial peritonitis (SBP). A high index of suspicion must be maintained when caring for patients with ascites, particularly those with acute clinical deterioration. Completely asymptomatic cases have been reported in as many as 30% of patients.
Fever and chills occur in as many as 80% of patients. Abdominal pain or discomfort is found in as many as 70% of patients.
Other signs and symptoms may include the following:
· Worsening or unexplained encephalopathy
· Diarrhea
· Ascites that does not improve following administration of diuretic medication
· Worsening or new-onset renal failure
IleusPhysical Examination
Abdominal tenderness is found in more than 50% of patients with spontaneous bacterial peritonitis. Findings can range from mild tenderness to overt rebound and guarding. In some cases, the abdominal examination findings mimic an acute intra-abdominal catastrophe requiring emergency surgical evaluation. Physical examination may also disclose hypotension (5-14% of patients) or signs of hepatic failure such as jaundice and angiomata.
Diagnostic Considerations
· Secondary bacterial peritonitis
· Perforated viscus
· Pyelonephritis
Clinical features do not distinguish secondary bacterial peritonitis from spontaneous bacterial peritonitis. However, patients with secondary bacterial peritonitis have a surgically treatable source of infection (eg, perforated duodenal ulcer, perinephric abscess).
In secondary bacterial peritonitis from free perforation of a viscus, the peritoneal fluid analysis characteristically shows an extremely elevated polymorphonuclear neutrophil count, multiple organisms (often including fungi and Enterococcus) on Gram stain and culture, and at least two of the following criteria
· Total protein greater than 1 g/dL
· Lactate dehydrogenase above the upper limit of normal for serum
· Glucose less than 50 mg/dL
Approach Considerations
All patients suspected of having spontaneous bacterial peritonitis (SBP) must undergo peritoneal fluid analysis while in the emergency department. Diagnostic paracentesis should be performed in all patients who do not have an indwelling peritoneal catheter and are suspected of having spontaneous bacterial peritonitis. In peritoneal dialysis patients with a peritoneal catheter, fluid should be withdrawn with sterile technique. Ultrasonography may aid paracentesis if ascites is minimally detectable or questionable.
Blood and urine cultures should be obtained in all patients suspected of having spontaneous bacterial peritonitis. Blood culture results are positive for the offending agent in as many as 33% of patients with spontaneous bacterial peritonitis and may help guide antibiotic therapy. Urine culture may also prove useful, since asymptomatic bacteruria has been suggested to predispose to the development of spontaneous bacterial peritonitis.
Abdominal flat plate, abdominal upright, and chest radiographs are obtained if a perforated viscus is considered.
Peritoneal Fluid Analysis
Peritoneal fluid analysis must be performed in any patient in whom spontaneous bacterial peritonitis (SBP) is considered. In patients undergoing peritoneal dialysis (PD), this can be accomplished by obtaining a sample of the dialysate. In patients without a peritoneal catheter, diagnostic paracentesis must be performed.
The examination of ascitic fluid for SBP has routinely involved sending the fluid for cell count, differential, and culture. It has been accepted that the results of aerobic and anaerobic bacterial cultures, used in conjunction with the cell count, are beneficial in guiding therapy for those with SBP
Recent data, though, suggest that ascitic fluid cultures have generally been shown to be of low yield with respect to altering management of patients with ascites. In addition, positive culture and sensitivity results obtained from emergency department testing have not been shown to result in appropriate adjustment of antibiotic therapy by inpatient physicians. The reasons for this may include inpatient physicians' distrust of the culture results and the difficulty in determining what constitutes a true pathogen in ascitic fluid cultures
The sensitivity of microbiologic studies has been reported to increase significantly with the direct inoculation of routine blood culture bottles at the bedside with 10 mL of ascitic fluid.
Ascitic fluid neutrophil count
An ascitic fluid neutrophil count of more than 500 cells/µL is the single best predictor of spontaneous bacterial peritonitis, with a sensitivity of 86% and specificity of 98%. Lowering the ascitic fluid neutrophil count to more than 250 cells/µL results in an increased sensitivity of 93% but a lower specificity of 94%. (For simplicity, a threshold of 250 cells/µL is used for the remainder of this discussion.)
An exciting new development in the rapid diagnosis of spontaneous bacterial peritonitis is the proposed use of reagent strips that detect leukocyte esterase, which can be read at the bedside using a portable spectrophotometric device. In a pilot study that compared the reagent strips with the manual laboratory polymorphonuclear leukocyte count, the strips achieved a 100% sensitivity in diagnosis of spontaneous bacterial peritonitis.
This diagnostic method holds promise in replacing manual cell counting, which is time-consuming and is often unavailable in many laboratories "after hours". Use of these reagent strips may result in a significant reduction of the time from paracentesis to presumptive diagnosis and antibiotic treatment of spontaneous bacterial peritonitis.
In a small cohort, the average time saved from dipstick to laboratory results ranged from 2.73 hours (dipstick to validated result from automated counter) to 3 hours (dipstick to validated manual cell count of ascitic fluid). Although promising, this diagnostic method has not been investigated in a large-scale study.
Other ascitic fluid studies
Other studies of ascitic fluid to be considered include the following:
· Cytology
· Lactate level
· pH
An ascites lactate level of more than 25 mg/dL was found to be 100% sensitive and specific in predicting active spontaneous bacterial peritonitis in a retrospective analysis. In the same study, the combination of an ascites fluid pH below 7.35 and polymorphonuclear neutrophil count above 500 cells/µL was 100% sensitive and 96% specific for spontaneous bacterial peritonitis.
A 2012 study investigated using leukocyte reagent strips in the emergency department as a means of expediting the diagnosis of spontaneous bacterial peritonitis.In this prospective study, 223 patients presenting with ascites and who had paracentesis performed in the emergency department had their peritoneal fluid sent for the usual diagnostic tests, but they also had the fluid dipped with both a Uri-Quick Clini 10 strip and Multistix 10SGA. Both had at least 90% positive predictive value and 94% negative predictive value for spontaneous bacterial peritonitis when compared with the criterion standard of peritoneal fluid Gram stain and culture—thus allowing a shorter interval between diagnosis and initiation of treatment.
Combined ascitic fluid neutrophil count and culture
Combining the results of the ascitic fluid polymorphonuclear neutrophil (PMN) count and the ascitic fluid culture yields the following subgroups:
· Spontaneous bacterial peritonitis
· Culture-negative neutrocytic ascites (probable spontaneous bacterial peritonitis)
· Monomicrobial nonneutrocytic bacterascites
Spontaneous bacterial peritonitis is noted when the PMN count is 250 cells/µL or higher, in conjunction with a positive bacterial culture result. As mentioned previously, one organism is usually identified on the culture in most cases. Obviously, these patients should receive antibiotic therapy.
Culture-negative neutrocytic ascites (probable spontaneous bacterial peritonitis) is noted when the ascitic fluid culture results are negative, but the PMN count is 250 cells/µL or higher. This may happen in as many as 50% of patients with SBP and may not actually represent a distinctly different disease entity. It may be the result of poor culturing techniques or late-stage resolving infection. Nonetheless, these patients should be treated just as aggressively as those with positive culture results.
Monomicrobial nonneutrocytic bacterascites exists when a positive culture result coexists with a PMN count of 250 cells/µL or fewer. Although this may often be the result of contamination of bacterial cultures, one study found that 38% of these patients subsequently develop spontaneous bacterial peritonitis.Therefore, monomicrobial nonneutrocytic bacterascites may represent an early form of spontaneous bacterial peritonitis.
All study patients described that eventually developed spontaneous bacterial peritonitis were symptomatic.For this reason, any patient suspected clinically of having spontaneous bacterial peritonitis in this setting must be treated.
Approach Considerations
A 2009 guideline from the American Association for the Study of Liver Diseases recommends that adult cirrhotic patients with ascitic fluid polymorphonuclear neutrophil (PMN) counts greater than 250 cells/ µL receive empiric antibiotic therapy (eg, an intravenous third-generation cephalosporin, preferably cefotaxime 2 g every 8 hours).As an alternative to intravenous cefotaxime, inpatients with cirrhosis can be treated with oral ofloxacin (400 mg twice per day), if none of the following contraindications are present
· Prior exposure to quinolones
· Vomiting
· Shock
· Grade II (or higher) hepatic encephalopathy
· Serum creatinine greater than 3 mg/dL
Patients with a peritoneal fluid PMN count greater than 500 cells/µL should universally be admitted and treated for spontaneous bacterial peritonitis, regardless of peritoneal fluid Gram stain result. Antibiotics should be initiated as soon as possible. The regimen can be chosen empirically, unless microbiologic studies further guide treatment.
For patients with a peritoneal fluid PMN count below 250 cells/µL, management depends upon the results of ascitic fluid cultures. All symptomatic patients should be admitted. Patients whose culture results are positive should be treated for spontaneous bacterial peritonitis. A select subset of patients who are completely asymptomatic yet have positive culture results may be managed without treatment but must undergo a follow-up paracentesis within 24-48 hours.
All symptomatic patients with a peritoneal fluid PMN count of 250-500 cells/µL should be admitted and treated for spontaneous bacterial peritonitis.
Probiotic therapy in conjunction with antimicrobial treatment does not improve efficacy in the treatment of spontaneous bacterial peritonitis, as was found in a double-blind, placebo-controlled, randomized-controlled trial.In this study, Pande et al found over a 28-month period that 110 patients who were randomized to either norfloxacin 400 mg with probiotics or placebo did not have improved efficacy in primary or secondary prophylaxis or in reducing mortality in cirrhotic patients with ascites.
Inpatient Care
For spontaneous bacterial peritonitis (SBP), a 10- to 14-day course of antibiotics is recommended. Although not required, a repeat peritoneal fluid analysis is recommended to verify declining PMN counts and sterilization of ascitic fluid.
If improvement in ascitic fluid or clinical condition does not occur within 48 hours, further evaluation is required to rule out bowel perforation or intra-abdominal abscess. Evaluation may include a combination of radiography, CT scanning, intraluminal contrast studies, or surgical exploration.
Medication Summary
The goals of pharmacotherapy in patients with spontaneous bacterial peritonitis (SBP) are to reduce morbidity and prevent complications. Antibiotics are initially chosen empirically, as these patients may die from overwhelming infection if treatment is delayed until culture results become available.
Probiotic therapy in conjunction with antimicrobial treatment does not improve efficacy in the treatment of spontaneous bacterial peritonitis, as was found in a double-blind, placebo-controlled, randomized-controlled trial.In this study, Pande et al found over a 28-month period that 110 patients who were randomized to either norfloxacin 400 mg with probiotics or placebo did not have improved efficacy in primary or secondary prophylaxis or in reducing mortality in cirrhotic patients with ascites.
Antimicrobials
Class Summary
Traditionally, a combination of an aminoglycoside and ampicillin was used to treat spontaneous bacterial peritonitis (SBP). This regimen affords excellent empiric coverage of more than 90% of cases of spontaneous bacterial peritonitis caused by gram-negative aerobes or gram-positive cocci.
More recently, the third-generation cephalosporin cefotaxime has been demonstrated to be as efficacious as the ampicillin/aminoglycoside combination, and it does not carry the increased risk of nephrotoxicity in cirrhotic patients. Cefotaxime does not cover enterococci (up to 5% of cases).
Cefotaxime (Claforan)
A third-generation cephalosporin with broad gram-negative spectrum, cefotaxime has lower efficacy against gram-positive organisms and higher efficacy against resistant organisms. Thus, it provides excellent empiric coverage of SBP. By binding to 1 or more penicillin-binding proteins, cefotaxime arrests bacterial cell wall synthesis and inhibits bacterial growth.
Gentamicin
Gentamicin is an aminoglycoside antibiotic effective against Pseudomonas aeruginosa; E coli; and Proteus, Klebsiella, and Staphylococcus species. Dosing regimens are numerous; adjust dose based on creatinine clearance (CrCl) and changes in volume of distribution. Gentamicin may be given IV or IM.
Ampicillin
Ampicillin interferes with bacterial cell wall synthesis during active multiplication, causing bactericidal activity against susceptible organisms.
Norfloxacin (Noroxin)
Norfloxacin is used for prophylaxis in the outpatient setting (400 mg/d). It is a fluoroquinolone with activity against pseudomonads, streptococci, MRSA, S epidermidis, and most gram-negative organisms, but it has no activity against anaerobes. It inhibits bacterial DNA synthesis and, consequently, growth.
Ciprofloxacin (Cipro)
Ciprofloxacin is used for prophylaxis in the outpatient setting (750 mg weekly). It is a fluoroquinolone that inhibits bacterial DNA synthesis and, consequently, growth, by inhibiting DNA gyrase and topoisomerases, which are required for replication, transcription, and translation of genetic material. Quinolones have broad activity against gram-positive and gram-negative aerobic organisms. This agent has no activity against anaerobes.
Sulfamethoxazole and trimethoprim (Bactrim DS, Septra DS)
This agent is used as prophylaxis in the outpatient setting (5 doses of double-strength trimethoprim-sulfamethoxazole per week (Monday through Friday). It inhibits bacterial growth by inhibiting the synthesis of dihydrofolic acid.
References
1. Lata J, Stiburek O, Kopacova M. Spontaneous bacterial peritonitis: a severe complication of liver cirrhosis. World J Gastroenterol. Nov 28 2009;15(44):5505-10.
2. Bert F, Noussair L, Lambert-Zechovsky N, Valla D. Viridans group streptococci: an underestimated cause of spontaneous bacterial peritonitis in cirrhotic patients with ascites. Eur J Gastroenterol Hepatol. Sep 2005;17(9):929-33.
3. Cholongitas E, Papatheodoridis GV, Lahanas A, Xanthaki A, Kontou-Kastellanou C, Archimandritis AJ. Increasing frequency of Gram-positive bacteria in spontaneous bacterial peritonitis. Liver Int. Feb 2005;25(1):57-61.
4. [Guideline] Runyon BA. Management of adult patients with ascites due to cirrhosis: an update. Hepatology. Jun 2009;49(6):2087-107.
5. Siple JF, Morey JM, Gutman TE, Weinberg KL, Collins PD. Proton pump inhibitor use and association with spontaneous bacterial peritonitis in patients with cirrhosis and ascites. Ann Pharmacother. Oct 2012;46(10):1413-8.
6. Riggio O, Angeloni S. Ascitic fluid analysis for diagnosis and monitoring of spontaneous bacterial peritonitis. World J Gastroenterol. Aug 21 2009;15(31):3845-50.
7. Chinnock B, Gomez R, Hendey GW. Peritoneal fluid cultures rarely alter management in patients with ascites. J Emerg Med. Jan 2011;40(1):21-4.
8. Gaya DR, David B Lyon T, et al. Bedside leucocyte esterase reagent strips with spectrophotometric analysis to rapidly exclude spontaneous bacterial peritonitis: a pilot study. Eur J Gastroenterol Hepatol. Apr 2007;19(4):289-95.
9. Téllez-Ávila FI, Chávez-Tapia NC, Franco-Guzmán AM, Uribe M, Vargas-Vorackova F. Rapid diagnosis of spontaneous bacterial peritonitis using leukocyte esterase reagent strips in emergency department: uri-quick clini-10SG® vs. Multistix 10SG®. Ann Hepatol. Sep-Oct 2012;11(5):696-9.
10. Runyon BA. Monomicrobial nonneutrocytic bacterascites: a variant of spontaneous bacterial peritonitis. Hepatology. Oct 1990;12(4 Pt 1):710-5.
11. Pande C, Kumar A, Sarin SK. Addition of probiotics to norfloxacin does not improve efficacy in the prevention of spontaneous bacterial peritonitis: a double-blind placebo-controlled randomized-controlled trial. Eur J Gastroenterol Hepatol. Jul 2012;24(7):831-9.
Spontaneous bacterial peritonitis
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Spontaneous bacterial peritonitis (SBP) is the development of peritonitis (infection in the abdominal cavity) despite the absence of an obvious source for the infection. It occurs almost exclusively in people with portal hypertension (increased pressure over the portal vein), usually as a result of cirrhosis of the liver. It can also occur in patients with nephrotic syndrome
The diagnosis of SBP requires paracentesis (aspiration of fluid with a needle) from the abdominal cavity.If the fluid contains bacteria or large numbers of neutrophil granulocytes (>250 cells/µL) (a type of white blood cells), infection is confirmed and antibiotics are required to avoid complications. In addition to antibiotics, infusions of albumin are usually administered.
Symptoms
Symptoms include fevers, chills, nausea, vomiting, abdominal tenderness and general malaise. Patients may complain of abdominal pain and worsening ascites. Thirteen percent of patients have no signs or symptoms. Hepatic encephalopathy may be the only manifestation of SBP; in the absence of a clear precipitant for the encephalopathy, all patients should undergo paracentesis, or sampling of the ascites fluid, in order to assess for SBP.
Pathogenesis
SBP is thought to result from a combination of factors inherent in cirrhosis and ascites, such as prolonged bacteremia secondary to compromised host defenses, intrahepatic shunting of colonized blood, and defective bactericidal activity within the ascitic fluid.Pharmacologic acid suppression has also been associated with SBP in patients with advanced cirrhosis Contrary to earlier theories, transmucosal migration of bacteria from the gut to the ascitic fluid is no longer considered to play a major role in the etiology of SBP.
With respect to compromised host defenses, patients with severe acute or chronic liver disease are often deficient in complement and may also have malfunctioning of the neutrophilic and reticuloendothelial systems.
As for the significance of ascitic fluid proteins, it was demonstrated that cirrhotic patients with ascitic protein concentrations below 1 g/dL were 10 times more likely to develop SBP than individuals with higher concentrations. It is thought that the antibacterial, or opsonic, activity of ascitic fluid is closely correlated with the protein concentration. Additional studies have confirmed the validity of the ascitic fluid protein concentration as the best predictor of the first episode of SBP.
Diagnosis
Diagnosis necessitates paracentesis (needle drainage of the ascitic fluid) and laboratory confirmation of ascitic neutrophils > 250/mm³.
Treatment
Antibiotics
After confirmation of SBP, patients need hospital admission for intravenous antibiotics (most often cefotaxime 2g IV Q8-12H for at least 5 days or ceftriaxone 2g IV Q24H). They will often also receive intravenous albumin. A repeat paracentesis in 48 hours is sometimes performed to ensure control of infection. Once patients have recovered from SBP, they require regular prophylactic antibiotics as long as they still have ascites.
Prokinetics
The addition of a prokinetic drug to an antibiotic regime reduces the incidence of spontaneous bacterial peritonitis possibly via decreasing small intestinal bacterial overgrowth.
Intravenous albumin
A randomized controlled trial found that intravenous albumin on the day of admission and on hospital day 3 can reduce renal impairment.
Prevention/screening
All cirrhotic patients might benefit from antibiotics (oral fluoroquinolone norfloxacin) if:
· Ascitic fluid protein <1.0 g/dL. Patients with fluid protein <15 g/L and either Child-Pugh score of at least 9 or impaired renal function may also benefit.
· Previous SBP
Cirrhotic patients admitted to the hospital should receive prophylactic antibiotics if:
· They have bleeding esophageal varices0] Epidemiology
Patients with ascites underwent routine paracentesis, the incidence of active SBP ranged from 10% to 27% at the time of hospital admission.
History
SBP was first described in 1964 by Prof Harold O. Conn.
References
1. Lata J, Stiburek O, Kopacova M (November 2009). "Spontaneous bacterial peritonitis: a severe complication of liver cirrhosis". World J. Gastroenterol. 15 (44): 5505–10. doi:10.3748/wjg.15.5505. PMC 2785051. PMID 19938187.
2. Hingorani SR, Weiss NS, Watkins SL (August 2002). "Predictors of peritonitis in children with nephrotic syndrome". Pediatr. Nephrol. 17 (8): 678–82. doi:10.1007/s00467-002-0890-6. PMID 12185481.
3. Chuang TF, Kao SC, Tsai CJ, Lee CC, Chen KS (January 1999). "Spontaneous bacterial peritonitis as the presenting feature in an adult with nephrotic syndrome". Nephrol. Dial. Transplant. 14 (1): 181–2. doi:10.1093/ndt/14.1.181. PMID 10052502.
4. Rimola A, García-Tsao G, Navasa M, et al. (January 2000). "Diagnosis, treatment and prophylaxis of spontaneous bacterial peritonitis: a consensus document. International Ascites Club". J. Hepatol. 32 (1): 142–53. doi:10.1016/S0168-8278(00)80201-9. PMID 10673079.
5. Koulaouzidis A, Bhat S, Saeed AA (March 2009). "Spontaneous bacterial peritonitis". World J. Gastroenterol. 15 (9): 1042–9. doi:10.3748/wjg.15.1042. PMC 2655193. PMID 19266595.
6. Runyon BA, Hoefs JC (1984). "Culture-negative neutrocytic ascites: a variant of spontaneous bacterial peritonitis". Hepatology 4 (6): 1209–11. doi:10.1002/hep.1840040619. PMID 6500513.
7. Gati GA, Deshpande A (2012). "Increased rate of spontaneous bacterial peritonitis among cirrhotic patients receiving pharmacologic acid suppression". Clinical Gastroenterology and Hepatology 4 (4): 422–27. doi:10.1016/j.cgh.2011.11.019. PMID 22155557.
8. Deshpande A, Pasupuleti V (2012). "Acid suppressive therapy is associated with spontaneous bacterial peritonitis in cirrhotic patients: a meta-analysis". Journal of Gastroenterology and Hepatology 28 (2): 235–42. doi:10.1111/jgh.12065. PMID 23190338.
9. Bajaj JS, Zadvornova Y (2009). "Association of Proton Pump Inhibitor Therapy With Spontaneous Bacterial Peritonitis in Cirrhotic Patients With Ascites". American Journal of Gastroenterology 104 (5): 1130–34. doi:10.1038/ajg.2009.80. PMID 19337238.
10. Runyon BA (1988). "Patients with deficient ascitic fluid opsonic activity are predisposed to spontaneous bacterial peritonitis". Hepatology 8 (3): 632–5. doi:10.1002/hep.1840080332. PMID 3371881.
11. Alaniz C, Regal RE (April 2009). "Spontaneous Bacterial Peritonitis: A Review of Treatment Options". P T 34 (4): 204–210. PMC 2697093. PMID 19561863.
12. Runyon BA (December 1986). "Low-protein-concentration ascitic fluid is predisposed to spontaneous bacterial peritonitis". Gastroenterology 91 (6): 1343–6. PMID 3770358.
13. Runyon BA, Morrissey RL, Hoefs JC, Wyle FA (1985). "Opsonic activity of human ascitic fluid: a potentially important protective mechanism against spontaneous bacterial peritonitis". Hepatology 5 (4): 634–7. doi:10.1002/hep.1840050419. PMID 4018735.
14. Hiyama, T.; Yoshihara, M.; Tanaka, S.; Haruma, K.; Chayama, K. (Apr 2009). "Effectiveness of prokinetic agents against diseases external to the gastrointestinal tract.". J Gastroenterol Hepatol 24 (4): 537–46. doi:10.1111/j.1440-1746.2009.05780.x. PMID 19220673.
15. Sort P, Navasa M, Arroyo V, et al. (1999). "Effect of intravenous albumin on renal impairment and mortality in patients with cirrhosis and spontaneous bacterial peritonitis". N. Engl. J. Med. 341 (6): 403–9. doi:10.1056/NEJM199908053410603. PMID 10432325.
16. Fernández J, Navasa M, Planas R, et al. (2007). "Primary prophylaxis of spontaneous bacterial peritonitis delays hepatorenal syndrome and improves survival in cirrhosis". Gastroenterology 133 (3): 818–24. doi:10.1053/j.gastro.2007.06.065. PMID 17854593.
17. Grangé JD, Roulot D, Pelletier G, et al. (1998). "Norfloxacin primary prophylaxis of bacterial infections in cirrhotic patients with ascites: a double-blind randomized trial". J. Hepatol. 29 (3): 430–6. doi:10.1016/S0168-8278(98)80061-5. PMID 9764990.
18. Soares-Weiser K, Brezis M, Tur-Kaspa R, Leibovici L (2002). "Antibiotic prophylaxis for cirrhotic patients with gastrointestinal bleeding". In Soares-Weiser, Karla. Cochrane database of systematic reviews (Online) (2): CD002907. doi:10.1002/14651858.CD002907. PMID 12076458.
19. Runyon BA (1988). "Spontaneous bacterial peritonitis: an explosion of information". Hepatology 8 (1): 171–5. doi:10.1002/hep.1840080131. PMID 3338704.
20. CONN HO (April 1964). "Spontaneous peritonitis and bacteremia in Laennec's cirrhosis caused by enteric organisms. A relatively common but rarely recognized syndrome" (PDF). Ann. Intern. Med. 60 (4): 568–80. PMID 14138877.
2. INTRODUCTION
3. Spontaneous bacterial peritonitis (SBP) is defined as an ascitic fluid infection without an evident intra-abdominal surgically-treatable source. The presence of SBP, which almost always occurs in patients with cirrhosis and ascites, is suspected because of suggestive signs and symptoms, such as fever, abdominal pain, or altered mental status , though some patients are asymptomatic and are detected when they undergo paracentesis after being admitted to the hospital for another reason. (See "Spontaneous bacterial peritonitis in adults: Clinical manifestations".)
4. This topic will review the diagnosis of SBP, as well as distinguishing SBP from secondary bacterial peritonitis or alcoholic hepatitis with ascites. The performance of paracentesis, the pathogenesis, clinical manifestations, and treatment of SBP, and the general evaluation of adults with ascites are discussed elsewhere. (See "Diagnostic and therapeutic abdominal paracentesis" and "Pathogenesis of spontaneous bacterial peritonitis" and "Spontaneous bacterial peritonitis in adults: Clinical manifestations" and "Spontaneous bacterial peritonitis in adults: Treatment and prophylaxis" and "Spontaneous bacterial peritonitis variants" and "Evaluation of adults with ascites".)
5. In 2013, the American Association for the Study of Liver Diseases (AASLD) updated its guideline on the management of adult patients with ascites due to cirrhosis The discussion that follows is consistent with that guideline.
6. OVERVIEW OF DIAGNOSTIC APPROACH
7. SBP should be suspected in patients with cirrhosis who develop signs or symptoms such as fever, abdominal pain, altered mental status, abdominal tenderness, or hypotension. In addition, patients with ascites admitted to the hospital for other reasons should also undergo paracentesis to look for evidence of SBP. A low clinical suspicion for SBP does not obviate the need for testing . (See "Spontaneous bacterial peritonitis in adults: Clinical manifestations", section on 'Clinical manifestations'.)
8. The importance of paracentesis was demonstrated in a review of a database of 17,711 patients with cirrhosis and ascites who were admitted to the hospital with a primary diagnosis of ascites or encephalopathy. Paracentesis was performed in 61 percent. Patients who underwent paracentesis had a lower in-hospital mortality rate than those who did not undergo paracentesis (6.5 versus 8.5 percent; adjusted odds ratio 0.55, 95% confidence interval 0.41-0.74).
Diagnosis of Spontaneous Bacterial Peritonitis
Introduction: Spontaneous bacterial peritonitis (SBP) occurs in up to 30% of patients with cirrhosis and has an estimated in-hospital mortality rate of 20%. The prevalence of SBP in cirrhotic outpatients is 1.5 to 3.5% and among inpatients is approximately 10%. In most instances, SBP results from translocation of bacteria from the intestinal lumen. Less often, SBP results from bacteremia that originates at a distant site, such as a urinary tract infection. Most cases of SBP are caused by gram-negative enteric organisms, such as Escherichia coli and Klebsiella pneumoniae. Risk factors for the development of SBP include ascitic fluid total protein less than 1 g/dL, gastrointestinal hemorrhage, and previous history of SBP.
Indications for Testing: In a patient with ascites, the presence of new onset fever (temperature greater than 37.8°C or 100°F), abdominal pain, hepatic encephalopathy, metabolic acidosis, renal failure, hypotension, diarrhea, paralytic ileus, hypothermia, leukocytosis, or other sign or symptom of infection should prompt a diagnostic paracentesis for ascitic fluid analysis and culture . Approximately 13% of patients with SBP can present without any symptoms. Because SBP is so commonly present at the time of any type of admission for a cirrhotic patient, a diagnostic paracentesis is recommended routinely for these patients at the time of admission. There is no need for transfusion of plasma or platelets prior to a diagnostic paracentesis, given the extremely low risk of hemorrhagic complications, except in the setting of disseminated intravascular coagulation or clinically apparent fibrinolysis.
Diagnostic Criteria: The diagnosis of confirmed spontaneous bacterial peritonitis requires an elevated ascitic fluid absolute polymorphonuclear leukocyte (PMN) count of at least 250 cells/mm3 (0.25 x 109/L) and a positive ascitic fluid bacterial culture without an obvious intra-abdominal source of infection. Ascitic fluid diagnostic testing should be performed before treatment is initiated as even a single dose of broad-spectrum antibiotics can lead to no growth on bacterial culture in 86% of cases. Approximately 1 mL of ascitic fluid should be injected into a “purple-top” EDTA tube for the cell count and differential analysis. In the case of a traumatic paracentesis, with the entry of blood into the ascitic fluid (typically ascitic red cells greater than 10,000 cells/mm3) the PMN count should be corrected by subtracting one PMN for every 250 red cells/mm3 from the absolute PMN count.
Bacterial Culture: Prior to administering antibiotics, ascitic fluid (at least 10 mL) should be inoculated directly into a blood culture bottle at the bedside, instead of sending the fluid to the laboratory in a syringe or container, since immediate inoculation improves the yield on bacterial culture from approximately 65% to 90%, when the ascitic fluid cell count is at least 250 cells/mm3 (0.25 x 109/L). Separate and simultaneous blood cultures should also be obtained, as up to 50% of patients with SBP have concomitant bacteremia.
Importance of Distinguishing SBP from Secondary Bacterial Peritonitis: It is important to distinguish SBP from secondary bacterial peritonitis because of the critical need to determine whether surgical intervention is needed. Specifically, mortality approaches 100% in patients with secondary bacterial peritonitis who receive treatment with antibiotics alone (without surgery) and mortality is approximately 80% in patients with cirrhosis and SBP who undergo an unnecessary exploratory laparotomy.
Diagnostic Tests for Distinguishing SBP from Secondary Bacterial Peritonitis: Diagnostic tests may help distinguish SBP from secondary bacterial peritonitis due to a perforated viscus or a loculated abscess. Characteristically, with secondary bacterial peritonitis, the fluid PMN count is at least 250 cells/mm3 (usually greater than several thousand) and multiple organisms, including fungi, are identified on Gram’s stain and isolated in culture. Laboratory diagnostic criteria for secondary bacterial peritonitis includes two of the following: ascitic fluid protein greater than 1 g/dL, lactate dehydrogenase higher than the upper limit of normal for serum, and glucose less than 50 mg/dL. In addition, ascitic fluid carcinoembryonic antigen greater than 5 ng/mL and alkaline phosphatase greater than 240 U/L have been shown to be associated with gut perforation. After 48 hours of appropriate antibiotic therapy, the ascitic fluid PMN count should decrease with SBP (typically below the pre-treatment level), but with secondary bacterial peritonitis the PMN count may increase. Patients who meet criteria for secondary bacterial peritonitis should undergo immediate abdominal imaging, and emergent laparotomy should be considered if perforation or a surgically treatable site of infection is identified or strongly suspected.
Other Diagnostic Tests on Ascitic Fluid: For an initial diagnostic paracentesis, other tests should be performed as clinically warranted on the remaining ascitic fluid. These tests can be submitted to the laboratory using a “red-top” tube and may include albumin, total protein, glucose, lactate dehydrogenase, amylase, and bilirubin. A serum-ascites gradient (SAAG) of 1.1 g/dL or greater is consistent with portal hypertension. A total protein level of less than 1.0 g/dL is associated with an increased risk of spontaneous bacterial peritonitis. Elevated total protein, low glucose concentration, and elevated lactate dehydrogenase ascitic values are seen in the setting of secondary bacterial peritonitis. Elevated ascitic amylase can be seen in pancreatitis and gut perforation. Biliary leakage into the peritoneum can be associated with increased ascitic fluid bilirubin concentration. For patients with a prior paracentesis, especially a recent paracenteis, most of these additional diagnostic tests will not need repeating.
Management of Spontaneous Bacterial Peritonitis
Treatment Regimens: Broad-spectrum antibiotic therapy is recommended for treatment of proven or suspected SBP and may be narrowed when susceptibility results become available . Cefotaxime (Claforan) administered 2 g IV every 8 hours (or similar third-generation cephalosporin for a total course of 5 days is the treatment of choice, as it covers the most common agents: Escherichia coli, Klebsiella pneumoniae, and Streptococcus pneumoniae. Cefotaxime has been shown to be successful in treating SBP in 77 to 98% of cases. Ceftriaxone (Rocephin) 1 g IV every 12 hours or 2 g every 24 hours for 5 days can be used in place of cefotaxime. Oral ofloxacin (Floxin) 400 mg PO twice a day for an average of 8 days was shown in one randomized controlled trial to be as effective as IV cefotaxime for hospitalized patients with SBP who do not have vomiting, shock, grade II or greater hepatic encephalopathy, or serum creatinine greater than 3 mg/dL. In a randomized trial involving patients who did not receive a fluoroquinolone for SBP prophylaxis, intravenous ciprofloxacin (Cipro) 200 mg IV every 12 hours for 2 days, followed by oral ciprofloxacin (500 mg PO every 12 hours for 5 days) was effective and more cost-effective than IV ceftazidime. Ciprofloxacin 400 mg IV every 12 hours or levofloxacin (Levaquin) 750 mg IV every 24 hours can be used in patients who have a penicillin allergy, but should be avoided in patients who have been receiving a fluoroquinolone for SBP prophylaxis. Studies have demonstrated resistance rates of approximately 30% in gram-negative infections to fluoroquinolones and trimethoprim-sulfamethoxazole (Bactrim, Septra), with particularly high rates in patients who have received fluoroquinolone prophylaxis; on the other hand, more than 90% of isolates in patients who have received fluoroquinolone prophylaxis still remain susceptible to cefotaxime. Extended spectrum antibiotics, such as carbapenems, may even be considered in nosocomial cases. In the end, the choice of treatment will depend on location of acquisition (community versus nosocomial), local resistance patterns, and culture sensitivity results when available.. Use of IV albumin should be reserved for patients with a serum creatinine greater than 1 mg/dL, blood urea nitrogen greater than 30 mg/dL, or total bilirubin greater than 4 mg/dL.
Follow-up Diagnostic Paracentesis: Follow-up ascitic fluid analysis is not necessary following treatment of SBP, unless something is unusual about the patient’s symptoms, fluid analysis, organism, or clinical course (for example, lack of clinical improvement). If the ascitic fluid PMN count has not declined by at least 25% after two days of antibiotic therapy, then the antibiotic coverage needs to be broadened to cover resistant organisms and secondary bacterial peritonitis needs to be considered. Patients with secondary bacterial peritonitis should undergo surgical intervention of the perforated viscus or drainage of the abscess and should be treated with broad-spectrum antibiotics, such as third-generation cephalosporins, with the addition of an antimicrobial agent that has good anaerobic coverage, such as metronidazole (Flagyl).
Indications for Spontaneous Bacterial Peritonitis Prophylaxis
Introduction: Most episodes of spontaneous bacterial peritonitis (SBP) are thought to result from bacterial translocation from the gut. Given the risk of resistance and alteration of gut flora, this long-term antibiotic prophylaxis should be reserved for high-risk patients only. Identified risk factors for the development of SBP include ascitic fluid total protein less than 1 g/dL, gastrointestinal hemorrhage, and a previous history of SBP.
Primary Prophylaxis of SBP: Cirrhotic patients with low protein ascites (less than 1.0 g/dL) and either impaired renal or liver function are at increased risk of developing SBP. Although controversy exists regarding the use of prophylactic antibiotics in patients who have never had SBP (primary prophylaxis), in one randomized trial, daily oral norfloxacin in patients with more advanced liver disease prevented the development of spontaneous bacterial peritonitis and hepatorenal syndrome and improved survival at 3 months when compared with those who received placebo. The AASLD guidelines suggest using long-term antibiotic prophylaxis in patients who have ascitic fluid total protein less than 1.5 g/dL and at least one of the following: serum creatinine greater than or equal to 1.2 mg/dL, blood urea nitrogen greater than or equal to 25 mg/dL, serum sodium less than or equal to 130 mEq/L, or Child-Turcotte-Pugh greater than or equal to 9 points (with bilirubin greater than or equal to 3 mg/dL).
Gastrointestinal Hemorrhage: Between 25% and 65% of cirrhotic patients with gastrointestinal bleeding develop bacterial infection, including spontaneous bacterial peritonitis. Antibiotic prophylaxis in this setting has been shown to decrease the risk of bacterial infections, the risk of re-bleeding, and overall mortality. In one meta-analysis of five trials, antibiotic prophylaxis in cirrhotics with gastrointestinal bleeding demonstrated a 9% increase in survival. Indeed, the use of prophylactic antibiotics in this setting is thought to have contributed significantly to the reduced mortality in patients with variceal bleeding (from 43% to 15% over the past two decades). In this situation, the AASLD guidelines recommend using a 7-day course of intravenous ceftriaxone or twice daily oral norfloxacin.
Regimens for Spontaneous Bacterial Peritonitis Prophylaxis
Primary and Secondary SBP Prophylaxis: Several studies have shown that oral norfloxacin 400 mg daily prevents spontaneous bacterial peritonitis in patients with low-protein ascites and those with previous history of spontaneous bacterial peritonitis (SBP). In one study, norfloxacin reduced SBP recurrence rates from 68% to 20%. Alternative regimens that have been studied include oral double-strength trimethoprim-sulfamethoxazole 5 doses per week or oral ciprofloxacin 750 mg once a week, but intermittent dosing may select for resistance. In addition, prolonged use antibiotic prophylaxis in this setting has led to the development of gram-negative bacterial resistance (to fluoroquinolones and trimethoprim-sulfamethoxazole), as well as an increased likelihood of developing gram-positive infections. Therefore, prophylaxis should be reserved for patients at high risk of developing SBP and daily dosing regimens are preferred. Daily long-term dosing with norfloxacin has proved superior to hospital-only administration of norfloxacin in the prevention of the first episode of SBP in cirrhotic patients with a serum total bilirubin greater than 2.5 mg/dL or ascitic fluid protein less than or equal to 1.5 g/dL. Therefore, long-term norfloxacin 400 mg daily is preferred. If norfloxacin is unavailable, reasonable alternatives include trimethoprim-sulfamethoxazole one double-strength tablet daily, ciprofloxacin 500 mg PO daily, or levofloxacin 250 mg PO daily
Infection Prophylaxis after Gastrointestinal Hemorrhage: Oral norfloxacin 400 mg twice daily for 7 days or IV ofloxacin 400 mg daily has been shown to prevent infection in patients with gastrointestinal hemorrhage. In addition, ceftriaxone 1 g IV daily for 7 days has been shown to be superior to norfloxacin for the prevention of infection in a randomized trial in patients with two of the following: ascites, severe malnutrition, encephalopathy, or bilirubin greater than 3 mg/dL. Thus, most experts prefer the use of IV ceftriaxone for infection prophylaxis after gastrointestinal hemorrhage in those patients with more advanced liver disease.
Summary Points
· New onset fever, abdominal pain, confusion, or other sign or symptom of infection in a cirrhotic patient should prompt an evaluation of the ascitic fluid for spontaneous bacterial peritonitis (SBP).
· Ascitic fluid should be sent for cell count and differential analysis and should be directly inoculated into blood culture bottles at the bedside.
· Patients with ascitic fluid PMN count greater than or equal to 250 cells/mm3 meet criteria for a presumptive diagnosis of SBP and should be treated with antibiotic therapy.
· Any cirrhotic patient with signs or symptoms concerning for SBP should be treated with antibiotic therapy regardless of ascitic fluid PMN count.
· Recommended therapy for SBP consists of IV cefotaxime 2 g IV every 8 to 12 hours (or a similar third generation cephalosporin) for a minimal duration of 5 days.
· Antibiotic prophylaxis for SBP should be given to cirrhotic patients with prior history of SBP or acute gastrointestinal bleeding, and should be considered in patients without history of SBP if the ascitic fluid total protein is less than 1.5 g/dL, in association with at least two of the following: serum creatinine greater than or equal to 1.2 mg/dL, blood urea nitrogen greater than or equal to 25 mg/dL, serum sodium less than or equal to 130 mEq/L or Child-Turcotte-Pugh greater than or equal to 9 points (with bilirubin greater than or equal to 3 mg/dL).
· Recommended regimens for primary and secondary SBP prophylaxis consist of oral norfloxacin 400mg daily or trimethoprim-sulfamethoxazole one double strength tablet daily. Daily dosing is preferred over intermittent dosing due to the increased risk of developing antimicrobial resistance with intermittent dosing.
· For patients with acute gastrointestinal hemorrhage, IV ceftriaxone 1 g IV daily (preferred in patients with more advanced liver disease) is recommended for a total duration of 7 days and has been shown to decrease the risk of infections, re-bleeding, and mortality. Once patients are stable with control of bleeding and resumption of oral intake, they may be transitioned to oral norfloxacin 400 mg twice daily to complete the 7-day course.
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Spontaneous bacterial peritonitis (SBP) is an acute bacterial infection of ascitic fluid. Generally, no source of the infecting agent is easily identifiable, but contamination of dialysate can cause the condition among those receiving peritoneal dialysis (PD).
Spontaneous bacterial peritonitis occurs in both children and adults and is a well-known and ominous complication in patients with cirrhosis.Of patients with cirrhosis who have spontaneous bacterial peritonitis, 70% are Child-Pugh class C. In these patients, the development of spontaneous bacterial peritonitis is associated with a poor long-term prognosis.
Once thought to occur only in those individuals with alcoholic cirrhosis, spontaneous bacterial peritonitis is now known to affect patients with cirrhosis from any cause. In addition, spontaneous bacterial peritonitis can occur as a complication of any disease state that produces the clinical syndrome of ascites, such as heart failure and Budd-Chiari syndrome. Children with nephrosis or systemic lupus erythematosus who have ascites have a high risk of developing spontaneous bacterial peritonitis.
Pathophysiology
The mechanism for bacterial inoculation of ascites has been the subject of much debate since Harold Conn first recognized the disorder in the 1960s. Enteric organisms have traditionally been isolated from more than 90% of infected ascites fluid in spontaneous bacterial peritonitis, suggesting that the GI tract is the source of bacterial contamination.
The preponderance of enteric organisms, in combination with the presence of endotoxin in ascitic fluid and blood, once favored the argument that spontaneous bacterial peritonitis was due to direct transmural migration of bacteria from an intestinal or hollow organ lumen, a phenomenon called bacterial translocation. However, experimental evidence suggests that direct transmural migration of microorganisms might not be the cause.
An alternative proposed mechanism for bacterial inoculation of ascites is hematogenous transmission in combination with an impaired immune system. Nonetheless, the exact mechanism of bacterial displacement from the GI tract into ascites fluid remains controversial.
A variety of factors contributes to peritoneal inflammation and bacterial growth in ascitic fluid. A key predisposing factor may be the intestinal bacterial overgrowth found in people with cirrhosis, mainly attributed to delayed intestinal transit time. Intestinal bacterial overgrowth, along with impaired phagocytic function, low serum and ascites complement levels, and decreased activity of the reticuloendothelial system, contributes to an increased number of microorganisms and decreased capacity to clear them from the bloodstream, resulting in their migration into and eventual proliferation within ascites fluid.
Interestingly, adults with spontaneous bacterial peritonitis typically have ascites, but most children with spontaneous bacterial peritonitis do not have ascites. The reason for and mechanism behind this is the source of ongoing investigation.
Etiology
Traditionally, three fourths of spontaneous bacterial peritonitis infections have been caused by aerobic gram-negative organisms (50% of these being Escherichia coli). The remainder has been due to aerobic gram-positive organisms (19% streptococcal species). E coli is displayed in the image below.
However, some data suggest that the percentage of gram-positive infections may be increasing.One study cites a 34.2% incidence of streptococci, ranking in second position after Enterobacteriaceae.Viridans group streptococci (VBS) accounted for 73.8% of these streptococcal isolates.
Anaerobic organisms are rare because of the high oxygen tension of ascitic fluid.
A single organism is noted in 92% of cases, and 8% of cases are polymicrobial.
Risk factors
Patients with cirrhosis who are in a decompensated state are at the highest risk of developing spontaneous bacterial peritonitis.Low complement levels are associated with the development of spontaneous bacterial peritonitis. Patients at greatest risk for spontaneous bacterial peritonitis have decreased hepatic synthetic function with associated low total protein level or prolonged prothrombin time (PT).
Patients with low protein levels in ascitic fluid (< 1 g/dL) have a 10-fold higher risk of developing spontaneous bacterial peritonitis than those with a protein level greater than 1 g/dL.
In a 2012 review by Siple et al,they show several case studies and cohorts of patients with cirrhosis and chronic liver disease who were on proton pump inhibitors (PPIs) for a prolonged duration who were at significantly increased risk for the development of spontaneous bacterial peritonitis. While prospective studies are needed on this subject, there appears to be a direct correlation between a lack of an acidic environment and portal hypertension to put these patients at increased risk for spontaneous bacterial peritonitis. Thus, in patients on long-term PPI therapy, the suspicion for infection should be heightened and the benefit of long-term PPI therapy should outweigh the risk for the development of spontaneous bacterial peritonitis.
Epidemiology
In patients with ascites, the frequency may be as high as 18%. This number has grown from 8% over the past 2 decades, most likely secondary to an increased awareness of spontaneous bacterial peritonitis and a lowered threshold to perform diagnostic paracentesis.
No race predilection is known for spontaneous bacterial peritonitis. In patients with ascites, both sexes are affected equally.
Although the etiology and incidence of hepatic failure differ between children and adults, in those individuals with ascites, the incidence of spontaneous bacterial peritonitis is roughly equal. Two peak ages for spontaneous bacterial peritonitis are characteristic in children: the first in the neonatal period and the second at age 5 years.
Prognosis
The mortality rate in patients with spontaneous bacterial peritonitis ranges from 40-70% in adult patients with cirrhosis. Rates are lower in children with nephrosis. Patients with concurrent renal insufficiency have been shown to be at a higher risk of mortality from spontaneous bacterial peritonitis than those without concurrent renal insufficiency. Mortality from spontaneous bacterial peritonitis may be decreasing among all subgroups of patients because of advances in its diagnosis and treatment.
History
A broad range of signs and symptoms are seen in spontaneous bacterial peritonitis (SBP). A high index of suspicion must be maintained when caring for patients with ascites, particularly those with acute clinical deterioration. Completely asymptomatic cases have been reported in as many as 30% of patients.
Fever and chills occur in as many as 80% of patients. Abdominal pain or discomfort is found in as many as 70% of patients.
Other signs and symptoms may include the following:
· Worsening or unexplained encephalopathy
· Diarrhea
· Ascites that does not improve following administration of diuretic medication
· Worsening or new-onset renal failure
IleusPhysical Examination
Abdominal tenderness is found in more than 50% of patients with spontaneous bacterial peritonitis. Findings can range from mild tenderness to overt rebound and guarding. In some cases, the abdominal examination findings mimic an acute intra-abdominal catastrophe requiring emergency surgical evaluation. Physical examination may also disclose hypotension (5-14% of patients) or signs of hepatic failure such as jaundice and angiomata.
Diagnostic Considerations
· Secondary bacterial peritonitis
· Perforated viscus
· Pyelonephritis
Clinical features do not distinguish secondary bacterial peritonitis from spontaneous bacterial peritonitis. However, patients with secondary bacterial peritonitis have a surgically treatable source of infection (eg, perforated duodenal ulcer, perinephric abscess).
In secondary bacterial peritonitis from free perforation of a viscus, the peritoneal fluid analysis characteristically shows an extremely elevated polymorphonuclear neutrophil count, multiple organisms (often including fungi and Enterococcus) on Gram stain and culture, and at least two of the following criteria
· Total protein greater than 1 g/dL
· Lactate dehydrogenase above the upper limit of normal for serum
· Glucose less than 50 mg/dL
Approach Considerations
All patients suspected of having spontaneous bacterial peritonitis (SBP) must undergo peritoneal fluid analysis while in the emergency department. Diagnostic paracentesis should be performed in all patients who do not have an indwelling peritoneal catheter and are suspected of having spontaneous bacterial peritonitis. In peritoneal dialysis patients with a peritoneal catheter, fluid should be withdrawn with sterile technique. Ultrasonography may aid paracentesis if ascites is minimally detectable or questionable.
Blood and urine cultures should be obtained in all patients suspected of having spontaneous bacterial peritonitis. Blood culture results are positive for the offending agent in as many as 33% of patients with spontaneous bacterial peritonitis and may help guide antibiotic therapy. Urine culture may also prove useful, since asymptomatic bacteruria has been suggested to predispose to the development of spontaneous bacterial peritonitis.
Abdominal flat plate, abdominal upright, and chest radiographs are obtained if a perforated viscus is considered.
Peritoneal Fluid Analysis
Peritoneal fluid analysis must be performed in any patient in whom spontaneous bacterial peritonitis (SBP) is considered. In patients undergoing peritoneal dialysis (PD), this can be accomplished by obtaining a sample of the dialysate. In patients without a peritoneal catheter, diagnostic paracentesis must be performed.
The examination of ascitic fluid for SBP has routinely involved sending the fluid for cell count, differential, and culture. It has been accepted that the results of aerobic and anaerobic bacterial cultures, used in conjunction with the cell count, are beneficial in guiding therapy for those with SBP
Recent data, though, suggest that ascitic fluid cultures have generally been shown to be of low yield with respect to altering management of patients with ascites. In addition, positive culture and sensitivity results obtained from emergency department testing have not been shown to result in appropriate adjustment of antibiotic therapy by inpatient physicians. The reasons for this may include inpatient physicians' distrust of the culture results and the difficulty in determining what constitutes a true pathogen in ascitic fluid cultures
The sensitivity of microbiologic studies has been reported to increase significantly with the direct inoculation of routine blood culture bottles at the bedside with 10 mL of ascitic fluid.
Ascitic fluid neutrophil count
An ascitic fluid neutrophil count of more than 500 cells/µL is the single best predictor of spontaneous bacterial peritonitis, with a sensitivity of 86% and specificity of 98%. Lowering the ascitic fluid neutrophil count to more than 250 cells/µL results in an increased sensitivity of 93% but a lower specificity of 94%. (For simplicity, a threshold of 250 cells/µL is used for the remainder of this discussion.)
An exciting new development in the rapid diagnosis of spontaneous bacterial peritonitis is the proposed use of reagent strips that detect leukocyte esterase, which can be read at the bedside using a portable spectrophotometric device. In a pilot study that compared the reagent strips with the manual laboratory polymorphonuclear leukocyte count, the strips achieved a 100% sensitivity in diagnosis of spontaneous bacterial peritonitis.
This diagnostic method holds promise in replacing manual cell counting, which is time-consuming and is often unavailable in many laboratories "after hours". Use of these reagent strips may result in a significant reduction of the time from paracentesis to presumptive diagnosis and antibiotic treatment of spontaneous bacterial peritonitis.
In a small cohort, the average time saved from dipstick to laboratory results ranged from 2.73 hours (dipstick to validated result from automated counter) to 3 hours (dipstick to validated manual cell count of ascitic fluid). Although promising, this diagnostic method has not been investigated in a large-scale study.
Other ascitic fluid studies
Other studies of ascitic fluid to be considered include the following:
· Cytology
· Lactate level
· pH
An ascites lactate level of more than 25 mg/dL was found to be 100% sensitive and specific in predicting active spontaneous bacterial peritonitis in a retrospective analysis. In the same study, the combination of an ascites fluid pH below 7.35 and polymorphonuclear neutrophil count above 500 cells/µL was 100% sensitive and 96% specific for spontaneous bacterial peritonitis.
A 2012 study investigated using leukocyte reagent strips in the emergency department as a means of expediting the diagnosis of spontaneous bacterial peritonitis.In this prospective study, 223 patients presenting with ascites and who had paracentesis performed in the emergency department had their peritoneal fluid sent for the usual diagnostic tests, but they also had the fluid dipped with both a Uri-Quick Clini 10 strip and Multistix 10SGA. Both had at least 90% positive predictive value and 94% negative predictive value for spontaneous bacterial peritonitis when compared with the criterion standard of peritoneal fluid Gram stain and culture—thus allowing a shorter interval between diagnosis and initiation of treatment.
Combined ascitic fluid neutrophil count and culture
Combining the results of the ascitic fluid polymorphonuclear neutrophil (PMN) count and the ascitic fluid culture yields the following subgroups:
· Spontaneous bacterial peritonitis
· Culture-negative neutrocytic ascites (probable spontaneous bacterial peritonitis)
· Monomicrobial nonneutrocytic bacterascites
Spontaneous bacterial peritonitis is noted when the PMN count is 250 cells/µL or higher, in conjunction with a positive bacterial culture result. As mentioned previously, one organism is usually identified on the culture in most cases. Obviously, these patients should receive antibiotic therapy.
Culture-negative neutrocytic ascites (probable spontaneous bacterial peritonitis) is noted when the ascitic fluid culture results are negative, but the PMN count is 250 cells/µL or higher. This may happen in as many as 50% of patients with SBP and may not actually represent a distinctly different disease entity. It may be the result of poor culturing techniques or late-stage resolving infection. Nonetheless, these patients should be treated just as aggressively as those with positive culture results.
Monomicrobial nonneutrocytic bacterascites exists when a positive culture result coexists with a PMN count of 250 cells/µL or fewer. Although this may often be the result of contamination of bacterial cultures, one study found that 38% of these patients subsequently develop spontaneous bacterial peritonitis.Therefore, monomicrobial nonneutrocytic bacterascites may represent an early form of spontaneous bacterial peritonitis.
All study patients described that eventually developed spontaneous bacterial peritonitis were symptomatic.For this reason, any patient suspected clinically of having spontaneous bacterial peritonitis in this setting must be treated.
Approach Considerations
A 2009 guideline from the American Association for the Study of Liver Diseases recommends that adult cirrhotic patients with ascitic fluid polymorphonuclear neutrophil (PMN) counts greater than 250 cells/ µL receive empiric antibiotic therapy (eg, an intravenous third-generation cephalosporin, preferably cefotaxime 2 g every 8 hours).As an alternative to intravenous cefotaxime, inpatients with cirrhosis can be treated with oral ofloxacin (400 mg twice per day), if none of the following contraindications are present
· Prior exposure to quinolones
· Vomiting
· Shock
· Grade II (or higher) hepatic encephalopathy
· Serum creatinine greater than 3 mg/dL
Patients with a peritoneal fluid PMN count greater than 500 cells/µL should universally be admitted and treated for spontaneous bacterial peritonitis, regardless of peritoneal fluid Gram stain result. Antibiotics should be initiated as soon as possible. The regimen can be chosen empirically, unless microbiologic studies further guide treatment.
For patients with a peritoneal fluid PMN count below 250 cells/µL, management depends upon the results of ascitic fluid cultures. All symptomatic patients should be admitted. Patients whose culture results are positive should be treated for spontaneous bacterial peritonitis. A select subset of patients who are completely asymptomatic yet have positive culture results may be managed without treatment but must undergo a follow-up paracentesis within 24-48 hours.
All symptomatic patients with a peritoneal fluid PMN count of 250-500 cells/µL should be admitted and treated for spontaneous bacterial peritonitis.
Probiotic therapy in conjunction with antimicrobial treatment does not improve efficacy in the treatment of spontaneous bacterial peritonitis, as was found in a double-blind, placebo-controlled, randomized-controlled trial.In this study, Pande et al found over a 28-month period that 110 patients who were randomized to either norfloxacin 400 mg with probiotics or placebo did not have improved efficacy in primary or secondary prophylaxis or in reducing mortality in cirrhotic patients with ascites.
Inpatient Care
For spontaneous bacterial peritonitis (SBP), a 10- to 14-day course of antibiotics is recommended. Although not required, a repeat peritoneal fluid analysis is recommended to verify declining PMN counts and sterilization of ascitic fluid.
If improvement in ascitic fluid or clinical condition does not occur within 48 hours, further evaluation is required to rule out bowel perforation or intra-abdominal abscess. Evaluation may include a combination of radiography, CT scanning, intraluminal contrast studies, or surgical exploration.
Medication Summary
The goals of pharmacotherapy in patients with spontaneous bacterial peritonitis (SBP) are to reduce morbidity and prevent complications. Antibiotics are initially chosen empirically, as these patients may die from overwhelming infection if treatment is delayed until culture results become available.
Probiotic therapy in conjunction with antimicrobial treatment does not improve efficacy in the treatment of spontaneous bacterial peritonitis, as was found in a double-blind, placebo-controlled, randomized-controlled trial.In this study, Pande et al found over a 28-month period that 110 patients who were randomized to either norfloxacin 400 mg with probiotics or placebo did not have improved efficacy in primary or secondary prophylaxis or in reducing mortality in cirrhotic patients with ascites.
Antimicrobials
Class Summary
Traditionally, a combination of an aminoglycoside and ampicillin was used to treat spontaneous bacterial peritonitis (SBP). This regimen affords excellent empiric coverage of more than 90% of cases of spontaneous bacterial peritonitis caused by gram-negative aerobes or gram-positive cocci.
More recently, the third-generation cephalosporin cefotaxime has been demonstrated to be as efficacious as the ampicillin/aminoglycoside combination, and it does not carry the increased risk of nephrotoxicity in cirrhotic patients. Cefotaxime does not cover enterococci (up to 5% of cases).
Cefotaxime (Claforan)
A third-generation cephalosporin with broad gram-negative spectrum, cefotaxime has lower efficacy against gram-positive organisms and higher efficacy against resistant organisms. Thus, it provides excellent empiric coverage of SBP. By binding to 1 or more penicillin-binding proteins, cefotaxime arrests bacterial cell wall synthesis and inhibits bacterial growth.
Gentamicin
Gentamicin is an aminoglycoside antibiotic effective against Pseudomonas aeruginosa; E coli; and Proteus, Klebsiella, and Staphylococcus species. Dosing regimens are numerous; adjust dose based on creatinine clearance (CrCl) and changes in volume of distribution. Gentamicin may be given IV or IM.
Ampicillin
Ampicillin interferes with bacterial cell wall synthesis during active multiplication, causing bactericidal activity against susceptible organisms.
Norfloxacin (Noroxin)
Norfloxacin is used for prophylaxis in the outpatient setting (400 mg/d). It is a fluoroquinolone with activity against pseudomonads, streptococci, MRSA, S epidermidis, and most gram-negative organisms, but it has no activity against anaerobes. It inhibits bacterial DNA synthesis and, consequently, growth.
Ciprofloxacin (Cipro)
Ciprofloxacin is used for prophylaxis in the outpatient setting (750 mg weekly). It is a fluoroquinolone that inhibits bacterial DNA synthesis and, consequently, growth, by inhibiting DNA gyrase and topoisomerases, which are required for replication, transcription, and translation of genetic material. Quinolones have broad activity against gram-positive and gram-negative aerobic organisms. This agent has no activity against anaerobes.
Sulfamethoxazole and trimethoprim (Bactrim DS, Septra DS)
This agent is used as prophylaxis in the outpatient setting (5 doses of double-strength trimethoprim-sulfamethoxazole per week (Monday through Friday). It inhibits bacterial growth by inhibiting the synthesis of dihydrofolic acid.
References
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5. Siple JF, Morey JM, Gutman TE, Weinberg KL, Collins PD. Proton pump inhibitor use and association with spontaneous bacterial peritonitis in patients with cirrhosis and ascites. Ann Pharmacother. Oct 2012;46(10):1413-8.
6. Riggio O, Angeloni S. Ascitic fluid analysis for diagnosis and monitoring of spontaneous bacterial peritonitis. World J Gastroenterol. Aug 21 2009;15(31):3845-50.
7. Chinnock B, Gomez R, Hendey GW. Peritoneal fluid cultures rarely alter management in patients with ascites. J Emerg Med. Jan 2011;40(1):21-4.
8. Gaya DR, David B Lyon T, et al. Bedside leucocyte esterase reagent strips with spectrophotometric analysis to rapidly exclude spontaneous bacterial peritonitis: a pilot study. Eur J Gastroenterol Hepatol. Apr 2007;19(4):289-95.
9. Téllez-Ávila FI, Chávez-Tapia NC, Franco-Guzmán AM, Uribe M, Vargas-Vorackova F. Rapid diagnosis of spontaneous bacterial peritonitis using leukocyte esterase reagent strips in emergency department: uri-quick clini-10SG® vs. Multistix 10SG®. Ann Hepatol. Sep-Oct 2012;11(5):696-9.
10. Runyon BA. Monomicrobial nonneutrocytic bacterascites: a variant of spontaneous bacterial peritonitis. Hepatology. Oct 1990;12(4 Pt 1):710-5.
11. Pande C, Kumar A, Sarin SK. Addition of probiotics to norfloxacin does not improve efficacy in the prevention of spontaneous bacterial peritonitis: a double-blind placebo-controlled randomized-controlled trial. Eur J Gastroenterol Hepatol. Jul 2012;24(7):831-9.
Spontaneous bacterial peritonitis
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Spontaneous bacterial peritonitis (SBP) is the development of peritonitis (infection in the abdominal cavity) despite the absence of an obvious source for the infection. It occurs almost exclusively in people with portal hypertension (increased pressure over the portal vein), usually as a result of cirrhosis of the liver. It can also occur in patients with nephrotic syndrome
The diagnosis of SBP requires paracentesis (aspiration of fluid with a needle) from the abdominal cavity.If the fluid contains bacteria or large numbers of neutrophil granulocytes (>250 cells/µL) (a type of white blood cells), infection is confirmed and antibiotics are required to avoid complications. In addition to antibiotics, infusions of albumin are usually administered.
Symptoms
Symptoms include fevers, chills, nausea, vomiting, abdominal tenderness and general malaise. Patients may complain of abdominal pain and worsening ascites. Thirteen percent of patients have no signs or symptoms. Hepatic encephalopathy may be the only manifestation of SBP; in the absence of a clear precipitant for the encephalopathy, all patients should undergo paracentesis, or sampling of the ascites fluid, in order to assess for SBP.
Pathogenesis
SBP is thought to result from a combination of factors inherent in cirrhosis and ascites, such as prolonged bacteremia secondary to compromised host defenses, intrahepatic shunting of colonized blood, and defective bactericidal activity within the ascitic fluid.Pharmacologic acid suppression has also been associated with SBP in patients with advanced cirrhosis Contrary to earlier theories, transmucosal migration of bacteria from the gut to the ascitic fluid is no longer considered to play a major role in the etiology of SBP.
With respect to compromised host defenses, patients with severe acute or chronic liver disease are often deficient in complement and may also have malfunctioning of the neutrophilic and reticuloendothelial systems.
As for the significance of ascitic fluid proteins, it was demonstrated that cirrhotic patients with ascitic protein concentrations below 1 g/dL were 10 times more likely to develop SBP than individuals with higher concentrations. It is thought that the antibacterial, or opsonic, activity of ascitic fluid is closely correlated with the protein concentration. Additional studies have confirmed the validity of the ascitic fluid protein concentration as the best predictor of the first episode of SBP.
Diagnosis
Diagnosis necessitates paracentesis (needle drainage of the ascitic fluid) and laboratory confirmation of ascitic neutrophils > 250/mm³.
Treatment
Antibiotics
After confirmation of SBP, patients need hospital admission for intravenous antibiotics (most often cefotaxime 2g IV Q8-12H for at least 5 days or ceftriaxone 2g IV Q24H). They will often also receive intravenous albumin. A repeat paracentesis in 48 hours is sometimes performed to ensure control of infection. Once patients have recovered from SBP, they require regular prophylactic antibiotics as long as they still have ascites.
Prokinetics
The addition of a prokinetic drug to an antibiotic regime reduces the incidence of spontaneous bacterial peritonitis possibly via decreasing small intestinal bacterial overgrowth.
Intravenous albumin
A randomized controlled trial found that intravenous albumin on the day of admission and on hospital day 3 can reduce renal impairment.
Prevention/screening
All cirrhotic patients might benefit from antibiotics (oral fluoroquinolone norfloxacin) if:
· Ascitic fluid protein <1.0 g/dL. Patients with fluid protein <15 g/L and either Child-Pugh score of at least 9 or impaired renal function may also benefit.
· Previous SBP
Cirrhotic patients admitted to the hospital should receive prophylactic antibiotics if:
· They have bleeding esophageal varices0] Epidemiology
Patients with ascites underwent routine paracentesis, the incidence of active SBP ranged from 10% to 27% at the time of hospital admission.
History
SBP was first described in 1964 by Prof Harold O. Conn.
References
1. Lata J, Stiburek O, Kopacova M (November 2009). "Spontaneous bacterial peritonitis: a severe complication of liver cirrhosis". World J. Gastroenterol. 15 (44): 5505–10. doi:10.3748/wjg.15.5505. PMC 2785051. PMID 19938187.
2. Hingorani SR, Weiss NS, Watkins SL (August 2002). "Predictors of peritonitis in children with nephrotic syndrome". Pediatr. Nephrol. 17 (8): 678–82. doi:10.1007/s00467-002-0890-6. PMID 12185481.
3. Chuang TF, Kao SC, Tsai CJ, Lee CC, Chen KS (January 1999). "Spontaneous bacterial peritonitis as the presenting feature in an adult with nephrotic syndrome". Nephrol. Dial. Transplant. 14 (1): 181–2. doi:10.1093/ndt/14.1.181. PMID 10052502.
4. Rimola A, García-Tsao G, Navasa M, et al. (January 2000). "Diagnosis, treatment and prophylaxis of spontaneous bacterial peritonitis: a consensus document. International Ascites Club". J. Hepatol. 32 (1): 142–53. doi:10.1016/S0168-8278(00)80201-9. PMID 10673079.
5. Koulaouzidis A, Bhat S, Saeed AA (March 2009). "Spontaneous bacterial peritonitis". World J. Gastroenterol. 15 (9): 1042–9. doi:10.3748/wjg.15.1042. PMC 2655193. PMID 19266595.
6. Runyon BA, Hoefs JC (1984). "Culture-negative neutrocytic ascites: a variant of spontaneous bacterial peritonitis". Hepatology 4 (6): 1209–11. doi:10.1002/hep.1840040619. PMID 6500513.
7. Gati GA, Deshpande A (2012). "Increased rate of spontaneous bacterial peritonitis among cirrhotic patients receiving pharmacologic acid suppression". Clinical Gastroenterology and Hepatology 4 (4): 422–27. doi:10.1016/j.cgh.2011.11.019. PMID 22155557.
8. Deshpande A, Pasupuleti V (2012). "Acid suppressive therapy is associated with spontaneous bacterial peritonitis in cirrhotic patients: a meta-analysis". Journal of Gastroenterology and Hepatology 28 (2): 235–42. doi:10.1111/jgh.12065. PMID 23190338.
9. Bajaj JS, Zadvornova Y (2009). "Association of Proton Pump Inhibitor Therapy With Spontaneous Bacterial Peritonitis in Cirrhotic Patients With Ascites". American Journal of Gastroenterology 104 (5): 1130–34. doi:10.1038/ajg.2009.80. PMID 19337238.
10. Runyon BA (1988). "Patients with deficient ascitic fluid opsonic activity are predisposed to spontaneous bacterial peritonitis". Hepatology 8 (3): 632–5. doi:10.1002/hep.1840080332. PMID 3371881.
11. Alaniz C, Regal RE (April 2009). "Spontaneous Bacterial Peritonitis: A Review of Treatment Options". P T 34 (4): 204–210. PMC 2697093. PMID 19561863.
12. Runyon BA (December 1986). "Low-protein-concentration ascitic fluid is predisposed to spontaneous bacterial peritonitis". Gastroenterology 91 (6): 1343–6. PMID 3770358.
13. Runyon BA, Morrissey RL, Hoefs JC, Wyle FA (1985). "Opsonic activity of human ascitic fluid: a potentially important protective mechanism against spontaneous bacterial peritonitis". Hepatology 5 (4): 634–7. doi:10.1002/hep.1840050419. PMID 4018735.
14. Hiyama, T.; Yoshihara, M.; Tanaka, S.; Haruma, K.; Chayama, K. (Apr 2009). "Effectiveness of prokinetic agents against diseases external to the gastrointestinal tract.". J Gastroenterol Hepatol 24 (4): 537–46. doi:10.1111/j.1440-1746.2009.05780.x. PMID 19220673.
15. Sort P, Navasa M, Arroyo V, et al. (1999). "Effect of intravenous albumin on renal impairment and mortality in patients with cirrhosis and spontaneous bacterial peritonitis". N. Engl. J. Med. 341 (6): 403–9. doi:10.1056/NEJM199908053410603. PMID 10432325.
16. Fernández J, Navasa M, Planas R, et al. (2007). "Primary prophylaxis of spontaneous bacterial peritonitis delays hepatorenal syndrome and improves survival in cirrhosis". Gastroenterology 133 (3): 818–24. doi:10.1053/j.gastro.2007.06.065. PMID 17854593.
17. Grangé JD, Roulot D, Pelletier G, et al. (1998). "Norfloxacin primary prophylaxis of bacterial infections in cirrhotic patients with ascites: a double-blind randomized trial". J. Hepatol. 29 (3): 430–6. doi:10.1016/S0168-8278(98)80061-5. PMID 9764990.
18. Soares-Weiser K, Brezis M, Tur-Kaspa R, Leibovici L (2002). "Antibiotic prophylaxis for cirrhotic patients with gastrointestinal bleeding". In Soares-Weiser, Karla. Cochrane database of systematic reviews (Online) (2): CD002907. doi:10.1002/14651858.CD002907. PMID 12076458.
19. Runyon BA (1988). "Spontaneous bacterial peritonitis: an explosion of information". Hepatology 8 (1): 171–5. doi:10.1002/hep.1840080131. PMID 3338704.
20. CONN HO (April 1964). "Spontaneous peritonitis and bacteremia in Laennec's cirrhosis caused by enteric organisms. A relatively common but rarely recognized syndrome" (PDF). Ann. Intern. Med. 60 (4): 568–80. PMID 14138877.
2. INTRODUCTION
3. Spontaneous bacterial peritonitis (SBP) is defined as an ascitic fluid infection without an evident intra-abdominal surgically-treatable source. The presence of SBP, which almost always occurs in patients with cirrhosis and ascites, is suspected because of suggestive signs and symptoms, such as fever, abdominal pain, or altered mental status , though some patients are asymptomatic and are detected when they undergo paracentesis after being admitted to the hospital for another reason. (See "Spontaneous bacterial peritonitis in adults: Clinical manifestations".)
4. This topic will review the diagnosis of SBP, as well as distinguishing SBP from secondary bacterial peritonitis or alcoholic hepatitis with ascites. The performance of paracentesis, the pathogenesis, clinical manifestations, and treatment of SBP, and the general evaluation of adults with ascites are discussed elsewhere. (See "Diagnostic and therapeutic abdominal paracentesis" and "Pathogenesis of spontaneous bacterial peritonitis" and "Spontaneous bacterial peritonitis in adults: Clinical manifestations" and "Spontaneous bacterial peritonitis in adults: Treatment and prophylaxis" and "Spontaneous bacterial peritonitis variants" and "Evaluation of adults with ascites".)
5. In 2013, the American Association for the Study of Liver Diseases (AASLD) updated its guideline on the management of adult patients with ascites due to cirrhosis The discussion that follows is consistent with that guideline.
6. OVERVIEW OF DIAGNOSTIC APPROACH
7. SBP should be suspected in patients with cirrhosis who develop signs or symptoms such as fever, abdominal pain, altered mental status, abdominal tenderness, or hypotension. In addition, patients with ascites admitted to the hospital for other reasons should also undergo paracentesis to look for evidence of SBP. A low clinical suspicion for SBP does not obviate the need for testing . (See "Spontaneous bacterial peritonitis in adults: Clinical manifestations", section on 'Clinical manifestations'.)
8. The importance of paracentesis was demonstrated in a review of a database of 17,711 patients with cirrhosis and ascites who were admitted to the hospital with a primary diagnosis of ascites or encephalopathy. Paracentesis was performed in 61 percent. Patients who underwent paracentesis had a lower in-hospital mortality rate than those who did not undergo paracentesis (6.5 versus 8.5 percent; adjusted odds ratio 0.55, 95% confidence interval 0.41-0.74).
Diagnosis of Spontaneous Bacterial Peritonitis
Introduction: Spontaneous bacterial peritonitis (SBP) occurs in up to 30% of patients with cirrhosis and has an estimated in-hospital mortality rate of 20%. The prevalence of SBP in cirrhotic outpatients is 1.5 to 3.5% and among inpatients is approximately 10%. In most instances, SBP results from translocation of bacteria from the intestinal lumen. Less often, SBP results from bacteremia that originates at a distant site, such as a urinary tract infection. Most cases of SBP are caused by gram-negative enteric organisms, such as Escherichia coli and Klebsiella pneumoniae. Risk factors for the development of SBP include ascitic fluid total protein less than 1 g/dL, gastrointestinal hemorrhage, and previous history of SBP.
Indications for Testing: In a patient with ascites, the presence of new onset fever (temperature greater than 37.8°C or 100°F), abdominal pain, hepatic encephalopathy, metabolic acidosis, renal failure, hypotension, diarrhea, paralytic ileus, hypothermia, leukocytosis, or other sign or symptom of infection should prompt a diagnostic paracentesis for ascitic fluid analysis and culture . Approximately 13% of patients with SBP can present without any symptoms. Because SBP is so commonly present at the time of any type of admission for a cirrhotic patient, a diagnostic paracentesis is recommended routinely for these patients at the time of admission. There is no need for transfusion of plasma or platelets prior to a diagnostic paracentesis, given the extremely low risk of hemorrhagic complications, except in the setting of disseminated intravascular coagulation or clinically apparent fibrinolysis.
Diagnostic Criteria: The diagnosis of confirmed spontaneous bacterial peritonitis requires an elevated ascitic fluid absolute polymorphonuclear leukocyte (PMN) count of at least 250 cells/mm3 (0.25 x 109/L) and a positive ascitic fluid bacterial culture without an obvious intra-abdominal source of infection. Ascitic fluid diagnostic testing should be performed before treatment is initiated as even a single dose of broad-spectrum antibiotics can lead to no growth on bacterial culture in 86% of cases. Approximately 1 mL of ascitic fluid should be injected into a “purple-top” EDTA tube for the cell count and differential analysis. In the case of a traumatic paracentesis, with the entry of blood into the ascitic fluid (typically ascitic red cells greater than 10,000 cells/mm3) the PMN count should be corrected by subtracting one PMN for every 250 red cells/mm3 from the absolute PMN count.
Bacterial Culture: Prior to administering antibiotics, ascitic fluid (at least 10 mL) should be inoculated directly into a blood culture bottle at the bedside, instead of sending the fluid to the laboratory in a syringe or container, since immediate inoculation improves the yield on bacterial culture from approximately 65% to 90%, when the ascitic fluid cell count is at least 250 cells/mm3 (0.25 x 109/L). Separate and simultaneous blood cultures should also be obtained, as up to 50% of patients with SBP have concomitant bacteremia.
Importance of Distinguishing SBP from Secondary Bacterial Peritonitis: It is important to distinguish SBP from secondary bacterial peritonitis because of the critical need to determine whether surgical intervention is needed. Specifically, mortality approaches 100% in patients with secondary bacterial peritonitis who receive treatment with antibiotics alone (without surgery) and mortality is approximately 80% in patients with cirrhosis and SBP who undergo an unnecessary exploratory laparotomy.
Diagnostic Tests for Distinguishing SBP from Secondary Bacterial Peritonitis: Diagnostic tests may help distinguish SBP from secondary bacterial peritonitis due to a perforated viscus or a loculated abscess. Characteristically, with secondary bacterial peritonitis, the fluid PMN count is at least 250 cells/mm3 (usually greater than several thousand) and multiple organisms, including fungi, are identified on Gram’s stain and isolated in culture. Laboratory diagnostic criteria for secondary bacterial peritonitis includes two of the following: ascitic fluid protein greater than 1 g/dL, lactate dehydrogenase higher than the upper limit of normal for serum, and glucose less than 50 mg/dL. In addition, ascitic fluid carcinoembryonic antigen greater than 5 ng/mL and alkaline phosphatase greater than 240 U/L have been shown to be associated with gut perforation. After 48 hours of appropriate antibiotic therapy, the ascitic fluid PMN count should decrease with SBP (typically below the pre-treatment level), but with secondary bacterial peritonitis the PMN count may increase. Patients who meet criteria for secondary bacterial peritonitis should undergo immediate abdominal imaging, and emergent laparotomy should be considered if perforation or a surgically treatable site of infection is identified or strongly suspected.
Other Diagnostic Tests on Ascitic Fluid: For an initial diagnostic paracentesis, other tests should be performed as clinically warranted on the remaining ascitic fluid. These tests can be submitted to the laboratory using a “red-top” tube and may include albumin, total protein, glucose, lactate dehydrogenase, amylase, and bilirubin. A serum-ascites gradient (SAAG) of 1.1 g/dL or greater is consistent with portal hypertension. A total protein level of less than 1.0 g/dL is associated with an increased risk of spontaneous bacterial peritonitis. Elevated total protein, low glucose concentration, and elevated lactate dehydrogenase ascitic values are seen in the setting of secondary bacterial peritonitis. Elevated ascitic amylase can be seen in pancreatitis and gut perforation. Biliary leakage into the peritoneum can be associated with increased ascitic fluid bilirubin concentration. For patients with a prior paracentesis, especially a recent paracenteis, most of these additional diagnostic tests will not need repeating.
Management of Spontaneous Bacterial Peritonitis
Treatment Regimens: Broad-spectrum antibiotic therapy is recommended for treatment of proven or suspected SBP and may be narrowed when susceptibility results become available . Cefotaxime (Claforan) administered 2 g IV every 8 hours (or similar third-generation cephalosporin for a total course of 5 days is the treatment of choice, as it covers the most common agents: Escherichia coli, Klebsiella pneumoniae, and Streptococcus pneumoniae. Cefotaxime has been shown to be successful in treating SBP in 77 to 98% of cases. Ceftriaxone (Rocephin) 1 g IV every 12 hours or 2 g every 24 hours for 5 days can be used in place of cefotaxime. Oral ofloxacin (Floxin) 400 mg PO twice a day for an average of 8 days was shown in one randomized controlled trial to be as effective as IV cefotaxime for hospitalized patients with SBP who do not have vomiting, shock, grade II or greater hepatic encephalopathy, or serum creatinine greater than 3 mg/dL. In a randomized trial involving patients who did not receive a fluoroquinolone for SBP prophylaxis, intravenous ciprofloxacin (Cipro) 200 mg IV every 12 hours for 2 days, followed by oral ciprofloxacin (500 mg PO every 12 hours for 5 days) was effective and more cost-effective than IV ceftazidime. Ciprofloxacin 400 mg IV every 12 hours or levofloxacin (Levaquin) 750 mg IV every 24 hours can be used in patients who have a penicillin allergy, but should be avoided in patients who have been receiving a fluoroquinolone for SBP prophylaxis. Studies have demonstrated resistance rates of approximately 30% in gram-negative infections to fluoroquinolones and trimethoprim-sulfamethoxazole (Bactrim, Septra), with particularly high rates in patients who have received fluoroquinolone prophylaxis; on the other hand, more than 90% of isolates in patients who have received fluoroquinolone prophylaxis still remain susceptible to cefotaxime. Extended spectrum antibiotics, such as carbapenems, may even be considered in nosocomial cases. In the end, the choice of treatment will depend on location of acquisition (community versus nosocomial), local resistance patterns, and culture sensitivity results when available.. Use of IV albumin should be reserved for patients with a serum creatinine greater than 1 mg/dL, blood urea nitrogen greater than 30 mg/dL, or total bilirubin greater than 4 mg/dL.
Follow-up Diagnostic Paracentesis: Follow-up ascitic fluid analysis is not necessary following treatment of SBP, unless something is unusual about the patient’s symptoms, fluid analysis, organism, or clinical course (for example, lack of clinical improvement). If the ascitic fluid PMN count has not declined by at least 25% after two days of antibiotic therapy, then the antibiotic coverage needs to be broadened to cover resistant organisms and secondary bacterial peritonitis needs to be considered. Patients with secondary bacterial peritonitis should undergo surgical intervention of the perforated viscus or drainage of the abscess and should be treated with broad-spectrum antibiotics, such as third-generation cephalosporins, with the addition of an antimicrobial agent that has good anaerobic coverage, such as metronidazole (Flagyl).
Indications for Spontaneous Bacterial Peritonitis Prophylaxis
Introduction: Most episodes of spontaneous bacterial peritonitis (SBP) are thought to result from bacterial translocation from the gut. Given the risk of resistance and alteration of gut flora, this long-term antibiotic prophylaxis should be reserved for high-risk patients only. Identified risk factors for the development of SBP include ascitic fluid total protein less than 1 g/dL, gastrointestinal hemorrhage, and a previous history of SBP.
Primary Prophylaxis of SBP: Cirrhotic patients with low protein ascites (less than 1.0 g/dL) and either impaired renal or liver function are at increased risk of developing SBP. Although controversy exists regarding the use of prophylactic antibiotics in patients who have never had SBP (primary prophylaxis), in one randomized trial, daily oral norfloxacin in patients with more advanced liver disease prevented the development of spontaneous bacterial peritonitis and hepatorenal syndrome and improved survival at 3 months when compared with those who received placebo. The AASLD guidelines suggest using long-term antibiotic prophylaxis in patients who have ascitic fluid total protein less than 1.5 g/dL and at least one of the following: serum creatinine greater than or equal to 1.2 mg/dL, blood urea nitrogen greater than or equal to 25 mg/dL, serum sodium less than or equal to 130 mEq/L, or Child-Turcotte-Pugh greater than or equal to 9 points (with bilirubin greater than or equal to 3 mg/dL).
Gastrointestinal Hemorrhage: Between 25% and 65% of cirrhotic patients with gastrointestinal bleeding develop bacterial infection, including spontaneous bacterial peritonitis. Antibiotic prophylaxis in this setting has been shown to decrease the risk of bacterial infections, the risk of re-bleeding, and overall mortality. In one meta-analysis of five trials, antibiotic prophylaxis in cirrhotics with gastrointestinal bleeding demonstrated a 9% increase in survival. Indeed, the use of prophylactic antibiotics in this setting is thought to have contributed significantly to the reduced mortality in patients with variceal bleeding (from 43% to 15% over the past two decades). In this situation, the AASLD guidelines recommend using a 7-day course of intravenous ceftriaxone or twice daily oral norfloxacin.
Regimens for Spontaneous Bacterial Peritonitis Prophylaxis
Primary and Secondary SBP Prophylaxis: Several studies have shown that oral norfloxacin 400 mg daily prevents spontaneous bacterial peritonitis in patients with low-protein ascites and those with previous history of spontaneous bacterial peritonitis (SBP). In one study, norfloxacin reduced SBP recurrence rates from 68% to 20%. Alternative regimens that have been studied include oral double-strength trimethoprim-sulfamethoxazole 5 doses per week or oral ciprofloxacin 750 mg once a week, but intermittent dosing may select for resistance. In addition, prolonged use antibiotic prophylaxis in this setting has led to the development of gram-negative bacterial resistance (to fluoroquinolones and trimethoprim-sulfamethoxazole), as well as an increased likelihood of developing gram-positive infections. Therefore, prophylaxis should be reserved for patients at high risk of developing SBP and daily dosing regimens are preferred. Daily long-term dosing with norfloxacin has proved superior to hospital-only administration of norfloxacin in the prevention of the first episode of SBP in cirrhotic patients with a serum total bilirubin greater than 2.5 mg/dL or ascitic fluid protein less than or equal to 1.5 g/dL. Therefore, long-term norfloxacin 400 mg daily is preferred. If norfloxacin is unavailable, reasonable alternatives include trimethoprim-sulfamethoxazole one double-strength tablet daily, ciprofloxacin 500 mg PO daily, or levofloxacin 250 mg PO daily
Infection Prophylaxis after Gastrointestinal Hemorrhage: Oral norfloxacin 400 mg twice daily for 7 days or IV ofloxacin 400 mg daily has been shown to prevent infection in patients with gastrointestinal hemorrhage. In addition, ceftriaxone 1 g IV daily for 7 days has been shown to be superior to norfloxacin for the prevention of infection in a randomized trial in patients with two of the following: ascites, severe malnutrition, encephalopathy, or bilirubin greater than 3 mg/dL. Thus, most experts prefer the use of IV ceftriaxone for infection prophylaxis after gastrointestinal hemorrhage in those patients with more advanced liver disease.
Summary Points
· New onset fever, abdominal pain, confusion, or other sign or symptom of infection in a cirrhotic patient should prompt an evaluation of the ascitic fluid for spontaneous bacterial peritonitis (SBP).
· Ascitic fluid should be sent for cell count and differential analysis and should be directly inoculated into blood culture bottles at the bedside.
· Patients with ascitic fluid PMN count greater than or equal to 250 cells/mm3 meet criteria for a presumptive diagnosis of SBP and should be treated with antibiotic therapy.
· Any cirrhotic patient with signs or symptoms concerning for SBP should be treated with antibiotic therapy regardless of ascitic fluid PMN count.
· Recommended therapy for SBP consists of IV cefotaxime 2 g IV every 8 to 12 hours (or a similar third generation cephalosporin) for a minimal duration of 5 days.
· Antibiotic prophylaxis for SBP should be given to cirrhotic patients with prior history of SBP or acute gastrointestinal bleeding, and should be considered in patients without history of SBP if the ascitic fluid total protein is less than 1.5 g/dL, in association with at least two of the following: serum creatinine greater than or equal to 1.2 mg/dL, blood urea nitrogen greater than or equal to 25 mg/dL, serum sodium less than or equal to 130 mEq/L or Child-Turcotte-Pugh greater than or equal to 9 points (with bilirubin greater than or equal to 3 mg/dL).
· Recommended regimens for primary and secondary SBP prophylaxis consist of oral norfloxacin 400mg daily or trimethoprim-sulfamethoxazole one double strength tablet daily. Daily dosing is preferred over intermittent dosing due to the increased risk of developing antimicrobial resistance with intermittent dosing.
· For patients with acute gastrointestinal hemorrhage, IV ceftriaxone 1 g IV daily (preferred in patients with more advanced liver disease) is recommended for a total duration of 7 days and has been shown to decrease the risk of infections, re-bleeding, and mortality. Once patients are stable with control of bleeding and resumption of oral intake, they may be transitioned to oral norfloxacin 400 mg twice daily to complete the 7-day course.
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