What was the aim of this Cochrane Review?
People with advanced liver disease (liver cirrhosis, or late-stage scarring of the liver with complications) are at risk of developing an abnormal build-up of fluid in the tummy, called ascites. This fluid may get infected with bacteria, without one knowing the cause. This is called 'spontaneous bacterial peritonitis'. It is important to prevent spontaneous bacterial peritonitis in people at high risk of developing it, because it is associated with a significant risk of death. Antibiotics are often used in people with advanced liver disease and ascites as a means to help prevent spontaneous bacterial peritonitis, but it is unclear whether they are effective and if effective, which antibiotic is the most effective.
We aimed to determine the best available antibiotic treatment (if any) for the prevention of spontaneous bacterial peritonitis in people with advanced liver disease. We collected and analysed all relevant research studies and found 29 randomised clinical trials (participants are randomly assigned to one of two treatment groups). During analysis of data, we used standard Cochrane techniques, allowing direct comparison of only two treatments at a time. We also used advanced techniques, allowing indirect comparisons of more than two treatments simultaneously (usually referred as 'network meta-analysis'). The aim was to gather reliable direct and indirect evidence.
Date of literature search
Only two small studies were conducted without flaws, and because of the very high uncertainty in the obtained analysis results, the authors could not say whether antibiotics work and, if they work, which one to use. Out of 1564 participants, 10% of people with cirrhosis and ascites developed spontaneous bacterial peritonitis, and out of 2169 participants, about 15% died within 12 months.
Funding source was unclear in 18 studies. Drug companies funded five studies. There were no concerns regarding the source of funding for the remaining six studies.
What did the review study?
We studied adults with advanced liver disease due to various causes, and who were undergoing preventive treatment to avoid developing spontaneous bacterial peritonitis. Participants received different antibiotics or no antibiotics. We excluded studies in people who had previously undergone liver transplantation, and where people received antibiotics for the treatment of spontaneous bacterial peritonitis or for any other reason. The average age of participants, when reported, ranged from 42 to 63 years. The administered antibiotic types were quinolones, rifamycins, sulfonamides, and aminoglycosides. The authors wanted to gather and analyse data on death, quality of life, serious and non-serious side effects, time to liver transplantation, time to development of spontaneous bacterial peritonitis, time to development of other complications of advanced liver disease, and length of hospital stay.
What were the main results of the review?
The 29 studies included a small number of participants (3896 participants). Study data were sparse. Twenty-three studies with 2587 participants provided data for analyses. The follow-up in the trials ranged from 1 to 12 months. The review shows that:
- of the 10 different antibiotics compared in the trials, norfloxacin and rifaximin were most commonly used;
- 15 of every 100 people died within 12 months, and 10 of every 100 people developed spontaneous bacterial peritonitis;
- giving preventive antibiotics may make no difference to the percentage of deaths or people with serious complications; however, potentially important differences cannot be ruled out;
- none of the trials reported quality of life or symptomatic development of spontaneous bacterial peritonitis;
- there was evidence showing that the percentage of people who developed spontaneous bacterial peritonitis as per laboratory criteria may be reduced with sulfonamides compared with no use of antibiotics (difficult to estimate how much reduction);
- there was evidence of differences in other outcomes such as any complications, liver transplantation, and other signs of liver failure, but these differences were not consistent. Therefore, the results are unreliable, and we cannot draw any conclusions about how effective antibiotics are;
- future well-designed trials are needed.
Quality of the evidence
We cannot draw any conclusions from these trials due to the sparse data.
Based on very low-certainty evidence, there is considerable uncertainty about whether antibiotic prophylaxis is beneficial, and if beneficial, which antibiotic prophylaxis is most beneficial in people with cirrhosis and ascites with low protein or history of spontaneous bacterial peritonitis.
Future randomised clinical trials should be adequately powered, employ blinding, avoid postrandomisation dropouts (or perform intention-to-treat analysis), and use clinically important outcomes such as mortality, health-related quality of life, and decompensation events.
Approximately 2.5% of all hospitalisations in people with liver cirrhosis are for spontaneous bacterial peritonitis. Spontaneous bacterial peritonitis is associated with significant short-term mortality; therefore, it is important to prevent spontaneous bacterial peritonitis in people at high risk of developing it. Antibiotic prophylaxis forms the mainstay preventive method, but this has to be balanced against the development of drug-resistant spontaneous bacterial peritonitis, which is difficult to treat, and other adverse events. Several different prophylactic antibiotic treatments are available; however, there is uncertainty surrounding their relative efficacy and optimal combination.
To compare the benefits and harms of different prophylactic antibiotic treatments for prevention of spontaneous bacterial peritonitis in people with liver cirrhosis using a network meta-analysis and to generate rankings of the different prophylactic antibiotic treatments according to their safety and efficacy.
We searched CENTRAL, MEDLINE, Embase, Science Citation Index Expanded, World Health Organization International Clinical Trials Registry Platform, and trials registers to November 2018 to identify randomised clinical trials in people with cirrhosis at risk of developing spontaneous bacterial peritonitis.
We included only randomised clinical trials (irrespective of language, blinding, or status) in adults with cirrhosis undergoing prophylactic treatment to prevent spontaneous bacterial peritonitis. We excluded randomised clinical trials in which participants had previously undergone liver transplantation, or were receiving antibiotics for treatment of spontaneous bacterial peritonitis or other purposes.
We performed a network meta-analysis with OpenBUGS using Bayesian methods and calculated the odds ratio, rate ratio, and hazard ratio (HR) with 95% credible intervals (CrI) based on an available-case analysis, according to National Institute of Health and Care Excellence Decision Support Unit guidance.
We included 29 randomised clinical trials (3896 participants; nine antibiotic regimens (ciprofloxacin, neomycin, norfloxacin, norfloxacin plus neomycin, norfloxacin plus rifaximin, rifaximin, rufloxacin, sparfloxacin, sulfamethoxazole plus trimethoprim), and 'no active intervention' in the review. Twenty-three trials (2587 participants) were included in one or more outcomes in the review. The trials that provided the information included people with cirrhosis due to varied aetiologies, with or without other features of decompensation, having ascites with low protein or previous history of spontaneous bacterial peritonitis. The follow-up in the trials ranged from 1 to 12 months. Many of the trials were at high risk of bias, and the overall certainty of evidence was low or very low. Overall, approximately 10% of trial participants developed spontaneous bacterial peritonitis and 15% of trial participants died.
There was no evidence of differences between any of the antibiotics and no intervention in terms of mortality (very low certainty) or number of serious adverse events (very low certainty). However, because of the wide CrIs, clinically important differences in these outcomes cannot be ruled out. None of the trials reported health-related quality of life or the proportion of people with serious adverse events.
There was no evidence of differences between any of the antibiotics and no intervention in terms of proportion of people with 'any adverse events' (very low certainty), liver transplantation (very low certainty), or the proportion of people who developed spontaneous bacterial peritonitis (very low certainty). The number of 'any' adverse events per participant was fewer with norfloxacin (rate ratio 0.74, 95% CrI 0.59 to 0.94; 4 trials, 546 participants; low certainty) and sulfamethoxazole plus trimethoprim (rate ratio 0.19, 95% CrI 0.02 to 0.81; 1 trial, 60 participants; low certainty) versus no active intervention. There was no evidence of differences between the other antibiotics and no intervention in the number of 'any' adverse events per participant (very low certainty). There were fewer other decompensation events with rifaximin versus no active intervention (rate ratio 0.61, 65% CrI 0.46 to 0.80; 3 trials, 575 participants; low certainty) and norfloxacin plus neomycin (rate ratio 0.06, 95% CrI 0.00 to 0.33; 1 trial, 22 participants; low certainty). There was no evidence of differences between the other antibiotics and no intervention in the number of decompensations events per participant (very low certainty). None of the trials reported health-related quality of life or development of symptomatic spontaneous bacterial peritonitis.
One would expect some correlation between the above outcomes, with interventions demonstrating effectiveness across several outcomes. This was not the case. The possible reasons for this include sparse data and selective reporting bias, which makes the results unreliable. Therefore, one cannot draw any conclusions from these inconsistent differences based on sparse data.
There was no evidence of any differences in the subgroup analyses (performed when possible) based on whether the prophylaxis was primary or secondary.
Funding: the source of funding for five trials were organisations who would benefit from the results of the study; six trials received no additional funding or were funded by neutral organisations; and the source of funding for the remaining 18 trials was unclear.