Introduction
Ascites is the major decompensating event in the natural history of cirrhosis.[1] Peritoneal infection is one of the most common sites of infection in cirrhosis.[2] Ascitic fluid infection without any evidence of a surgically treatable intra-abdominal
source is termed as spontaneous bacterial peritonitis (SBP).[2] The diagnosis of SBP is established by demonstrating ≥ 250/mm3 polymorphonuclear cells on ascitic fluid analysis (performed with strict aseptic
precautions) irrespective of the culture positivity in a cirrhosis patient presenting
with or without symptoms of peritoneal infection, that is, fever, abdominal pain,
tenderness, diarrhea, or ileus.[3] The prevalence of SBP is approximately 1.2 to 3.5% in outpatients and 10 to 27%
in hospitalized patients with cirrhosis.[4] SBP is an indication for liver transplantation as the recurrence rate is as high
as 70% at 1 year and is associated with high mortality.[5] Therefore, selective intestinal decontamination (SID) with antibiotics may reduce
the incidence of SBP and positively impact the course of cirrhosis patients. In this
commentary, we will discuss the indications, advantages, and disadvantages of prophylactic
antibiotics to prevent SBP.
Why is Prophylaxis Required in Cirrhosis Patients?
Why is Prophylaxis Required in Cirrhosis Patients?
Gram-negative bacilli (GNB) belonging to Enterobacteriaceae are the frequent cause of SBP, although recently, there has been a rise in Gram-positive
cocci infections.[2] Common organisms causing SBP include Escherichia coli, Klebsiella pneumoniae, enterococci, and Staphylococcus aureus.[3] Cirrhosis-associated immune dysfunction, impaired intestinal permeability, and bacterial
overgrowth increase the risk of bacterial translocation and endotoxemia.[6] Infections in cirrhosis can rapidly worsen liver disease and culminate in acute-on-chronic
liver failure (ACLF) with multiorgan dysfunction. SID with antibiotics can reduce
bacterial translocation, contain endotoxemia, reduce the incidence of infections,
and improve outcomes.
Who Can Benefit the most from Antibiotic Prophylaxis?
Who Can Benefit the most from Antibiotic Prophylaxis?
The seminal study by Llach et al demonstrated that patients with ascitic fluid protein < 1 g/dL
are at the increased risk of developing SBP.[7] Similarly, the recurrence of SBP was also dependent on the ascitic fluid protein.[5] Based on several studies, Fernández et al randomized patients with ascitic fluid
protein < 1.5 g/dL with renal or hepatic failure to receive norfloxacin or placebo.[8] This was the first study to demonstrate a survival benefit. The incidence of SBP
was 7% in the norfloxacin arm compared with 61% in the placebo arm. Similarly, the
incidence of hepatorenal syndrome was 28% in the norfloxacin arm compared with 41%
in the placebo arm. Norfloxacin was also reported to improve 3-month (94% vs. 62%)
and 1-year (60% vs. 48%) survival compared with placebo. This study formed the basis
to recommend primary prophylaxis with norfloxacin for patients with decompensated
cirrhosis with low ascitic fluid protein (< 1.5 g/dL) with liver failure (defined
as serum bilirubin ≥ 3.0 mg/dL with Child-Pugh score ≥ 9) or renal dysfunction (defined
as blood urea nitrogen ≥ 25 mg/dL or serum creatinine ≥ 1.2 mg/dL or serum sodium
≤ 130 mmol/dL).[2]
[8] The same was upheld by the recent randomized controlled trial (RCT) by Moreau et
al which demonstrated significant mortality benefit with norfloxacin in patients with
ascitic fluid protein < 1.5 g/dL but not in patients with ascitic fluid protein > 1.5 g/dL.[9]
Approximately 30 to 40% of patients with variceal bleed have bacterial infections,
increasing the risk of variceal rebleed and mortality.[10] Intravenous ceftriaxone and norfloxacin are equally effective in preventing infections
in patients with variceal bleed. Secondary prophylaxis is indicated for patients with
a history of SBP. There have been several studies evaluating the role of antibiotics
in preventing SBP. Some of the landmark RCTs are discussed in [Supplementary Table S1] (available in the online version). A recent study also demonstrated the efficacy
of norfloxacin in reducing bacterial infections in patients with ACLF.[11] SBP was less frequently noted in ACLF patients.[12] Although norfloxacin could not prolong the transplant-free survival in patients
with ACLF, norfloxacin led to a reduction in the incidence of hepatic encephalopathy
and contained the endotoxin rise. Furthermore, the trial highlighted the beneficial
role of prophylactic norfloxacin in patients with alcohol-associated hepatitis receiving
steroid therapy. Lastly, the dose of norfloxacin needs to be adjusted only in patients
with estimated glomerular filtration rate < 30 mL/min/1.73 m2 and those on dialysis.
What are the Other Drugs for Prevention of SBP?
What are the Other Drugs for Prevention of SBP?
Norfloxacin has low systemic bioavailability due to low solubility and low permeability.
Furthermore, norfloxacin has been proven to prevent SBP and infections in patients
with gastrointestinal hemorrhage. Thus making norfloxacin an ideal choice for SID.[11] Therefore, norfloxacin is the most commonly used drug. Food and Drug Administration
discontinued norfloxacin as the company manufacturing norfloxacin discontinued the
medication. There were no safety concerns regarding the drug. Several other drugs
have equal efficacy as norfloxacin and are frequently used in countries where norfloxacin
is unavailable.
Once-weekly rufloxacin, a long-acting quinolone, was assessed against daily norfloxacin.
Norfloxacin was reported to be more effective than rufloxacin in preventing the recurrence
of peritonitis due to Enterobacteriaceae.[13] Rufloxacin is a well-known effective drug for respiratory infections and is not
recommended to prevent SBP. Administered once weekly, 750 mg of ciprofloxacin is as
effective as norfloxacin in preventing SBP.[14] However, with an elimination half-life of 3 to 6 hours, the benefit of once-weekly
ciprofloxacin to prevent SBP needs to be assessed in further studies.
Trimethoprim-sulfamethoxazole (TMP-SMX) is a safer alternative to norfloxacin and
is a preferred choice when norfloxacin is unavailable or for patients who are intolerant
to fluoroquinolones. Few studies comparing TMP-SMX and norfloxacin have demonstrated
both to be equally effective in preventing SBP. However, skin rashes, cytopenias,
and deterioration in renal function with TMP-SMX require frequent monitoring ([Supplementary Table S1], available in the online version).
Rifaximin, a nonabsorbable gut sterilizer, has excellent efficacy in preventing the
recurrence of hepatic encephalopathy.[15] Four RCTs have evaluated the role of rifaximin in the primary and secondary prevention
of SBP ([Supplementary Table S2], available in the online version). A meta-analysis including 13 studies and 1,703
patients concluded that rifaximin has a protective role in prophylaxis for SBP; however,
the quality of the evidence was very low.[16] A recent high-quality randomized study reported rifaximin to be more effective in
preventing recurrence (secondary prophylaxis) of SBP but not occurrence (primary prophylaxis).[17] Although rifaximin and norfloxacin have similar immunomodulatory effects in patients
with cirrhosis, the cost of twice-daily dosing of rifaximin is a major limiting factor.[18] Future studies should compare norfloxacin and rifaximin with respect to preventing
extraperitoneal infection, fungal peritonitis, infection by multidrug-resistant organisms
(MDROs), change in endotoxin levels, and/or prevention of encephalopathy. In the absence
of any such added benefit, in the author's opinion, the utility of rifaximin in SBP
prophylaxis (especially primary prophylaxis) remains limited and cannot be recommended
till further evidence.
Several meta-analyses have assessed the role of antibiotic prophylaxis in preventing
SBP and improving survival[16]
[19]
[20]
[21]
[22]
[23]
[24] ([Table 1]). The latest meta-analysis by Mücke et al demonstrated that norfloxacin prophylaxis
led to a decrease in the incidence of SBP. However, the efficacy of norfloxacin in
preventing death decreased over a period.[21] The authors attributed this to the rise in MDROs in recent years. Nevertheless,
SID with antibiotics remains the cornerstone of management for patients with cirrhosis.
Table 1
Major meta-analysis comparing different regimens in the past 5 years
|
Author, year
|
Inclusion
|
Number of studies and patients
|
Primary prophylaxis
|
Secondary prophylaxis
|
Conclusions/comments
|
|
Soni et al 2020[20]
|
Randomized studies evaluating the role of antibiotics in adult cirrhotic patients
with ascites for primary or secondary prophylaxis of SBP
|
10 and 973 patients for primary prophylaxis; nine studies and 737 patients in secondary
prophylaxis
|
NFX daily; rifaximin daily, and NFX and rifaximin alternate months were effective
|
Rifaximin daily was effective
|
Rifaximin effective both for primary and secondary prevention of SBP.
Included only one study on rifaximin. Needs large RCTs
|
|
Komolafe et al 2020[19]
|
Randomized clinical trials in adults with cirrhosis undergoing prophylactic treatment
to prevent spontaneous bacterial peritonitis
|
23 trials, 2,587 participants
|
Any adverse events per participant were fewer with NFX and TMP-SMX versus no active
intervention. There were fewer other decompensation events with rifaximin versus no
active intervention and NFX plus neomycin
|
|
The authors highlighted the need to assess the effect of antibiotics on health-related
quality of life and decompensation events.
Similar to other Cochrane reviews, the current review failed to demonstrate any benefit
with antibiotics, contrary to several other studies, and pointed to a high risk of
bias from the included studies
|
|
Mücke et al 2020[21]
|
Randomized controlled trials of patients with liver cirrhosis that assessed SBP occurrence/recurrence
during antibiotic prophylaxis with the common antibiotic agents
|
12 trials, 1,626 patients
|
NFX reduced the incidence rate of SBP and death
|
NFX was not superior to other antibiotics
|
On meta-regression, NFX was most effective at bilirubin levels between 3 and 5 mg/d.
The authors raised the concern of MDROs as the cause of decreasing efficacy of NFX
over time
|
|
Facciorusso et al 2019[22]
|
Randomized controlled trials comparing antibiotic treatments (NFX, ciprofloxacin,
TMP-SMX, and rifaximin) with each other or placebo
|
10 studies
|
Moderate quality evidence supported use of NFX and ciprofloxacin in primary prophylaxis.
Low-quality evidence suggests superiority of rifaximin. No difference among various
antibiotics
|
|
NFX could reduce mortality and the incidence of SBP but not other site infections.
Ciprofloxacin has unclear mortality benefit
|
|
Menshawy et al 2019[23]
|
Studies involving use of rifaximin for prophylaxis
|
Six studies involving 973 patients
|
Rifaximin plus NFX had less incidence of SBP and hepatic encephalopathy than the only
NFX-based regimen group. No significant difference between rifaximin and NFX in terms
of frequency of SBP and success rate of primary prevention of SBP
|
|
Rifaximin is as effective as NFX based on a limited number of studies
|
|
Kamal et al 2017[16]
|
Comparative studies evaluating the effect of rifaximin on the occurrence of SBP and
HRS
|
13 studies (4 RCTs and 9 observational studies), 1,703 patients
|
Rifaximin is effective on subgroup analysis, including four studies in reducing the
occurrence of SBP
|
Rifaximin effective in reducing recurrence based on two studies
|
Rifaximin also reduced the incidence of hepatorenal syndrome.
The study included observational studies, and the quality of evidence was very low
|
|
Goel et al 2017[24]
|
Studies on the association between rifaximin and SBP
|
5 studies, 555 patients
|
Rifaximin failed to reduce the occurrence of SBP compared with systemic antibiotics
on sensitivity analysis
|
Rifaximin reduced the recurrence of SBP compared with systemic antibiotics on sensitivity
analysis
|
The number of studies included was low to recommend rifaximin for prophylaxis over
NFX
|
Abbreviations: HRS, hepatorenal syndrome; MDRO, multidrug-resistant organism; NFX,
Norfloxacin; RCT, randomized controlled trial; SBP, spontaneous bacterial peritonitis;
TMP-SMX, trimethoprim-sulfamethoxazole.
How to Manage Recurrent SBP?
How to Manage Recurrent SBP?
Antibiotic prophylaxis is less effective in patients harboring MDROs at baseline.
MDROs are a common cause of recurrent SBP and are associated with higher mortality.
Bedside ascitic fluid culture in (both aerobic and anaerobic) blood culture bottles
before initiating antibiotics is more valuable in SBP as it can guide the therapy.
Broad-spectrum antibiotics (piperacillin-tazobactam in countries where MDROs prevalence
is low and carbapenems where MDROs prevalence is high) are the preferred drug of choice.
Further studies are required to assess a suitable prophylactic antibiotic for patients
harboring MDROs.
Can any Vaccination Prevent SBP?
Can any Vaccination Prevent SBP?
Streptococcus pneumoniae-related SBP patients are more likely to be community-acquired
infections, frequently present with concurrent bacteremia, and have a higher risk
of variceal bleed.[25] Pneumococcal vaccination may reduce the incidence of SBP due to Streptococcus pneumonia.
Universal vaccination strategies should be followed in all patients with cirrhosis
to improve the outcomes.[4]
What are the Disadvantages of Prophylactic Antibiotics in Cirrhosis Population?
What are the Disadvantages of Prophylactic Antibiotics in Cirrhosis Population?
Despite the several advantages of once-daily norfloxacin, the drug is associated with
few drawbacks. Norfloxacin prophylaxis increases the risk of quinolone-resistant GNB
infections and infections by Gram-positive organisms.[26] Few reports have suggested an increased risk of Clostridium difficile infection with norfloxacin prophylaxis.[27] A recent study also reported an increased risk of Candida albicans infection in patients receiving prophylactic norfloxacin.[11] The burden of MDROs is rapidly growing. The incidence of MDROs among patients with
cirrhosis ranges between 20 and 34% globally and 70% in India.[28] Although initial studies reported an increased risk of MDROs with prophylactic norfloxacin,
some major studies have contradicted and suggested that even long-term norfloxacin
prophylaxis is safe in patients with cirrhosis without the added risk of MDROs.[9]
[28] Lastly, tuberculosis is highly prevalent in Asia and fluoroquinolones are well-known
second-line antitubercular drugs. Empirical treatment with fluoroquinolones may lead
to development of resistant tuberculosis. Therefore, we strongly suggest excluding
tuberculosis before prophylactic fluoroquinolone initiation.[29]
How to Reduce the Incidence of MDROs?
How to Reduce the Incidence of MDROs?
Some measures to reduce the burden of MDROs include avoiding unnecessary: hospital
admissions, prolonged hospital stay, invasive procedures, antibiotic treatment (as
an over-the-counter drug), and prolonged proton-pump inhibitor therapy. Universal
precautions, including hand hygiene, must be adhered to while caring for these immunocompromised
patients. Cirrhosis patients should be frequently screened for MDROs through nasal
and rectal swabs. Strict local antibiotic policies and antibiotic stewardship are
required to reduce the incidence of MDROs. Nonantibiotic methods to minimize the burden
of infections are necessary. Beta-blockers,[30] simvastatin,[31] and immunonutrition[32] are some of the known nonantibiotic interventions to reduce the incidence of infections.[33] Recent studies have reported fecal (intestinal) microbiota transplantation to be
safe and effective in modifying the gut antibiotic resistance genes and may be the
future strategy to prevent MDROs.[34]
Conclusion
Infections, especially SBP, are the leading cause of morbidity and mortality in patients
with cirrhosis. Prophylactic antibiotics can reduce the incidence of infections and
prolong survival in carefully selected patients. Appropriate antibiotic prescription
is low for primary and secondary SBP prevention. Clinicians need to be aware of such
indications for antibiotic prophylaxis to improve the outcomes for patients with cirrhosis
([Fig. 1]). Norfloxacin is the preferred antibiotic due to lack of safety concerns and more
patient acceptability. Rifaximin appears to be a promising agent in the prevention
of SBP.
Fig. 1 Prophylactic antibiotic indications and duration of therapy for patients with cirrhosis.
ACLF, acute-on-chronic liver failure; TMP-SMX, trimethoprim-sulfamethoxazole.
