https://orcid.org/0009-0004-8371-7732
Abstract
Antibiotic prophylaxis for spontaneous bacterial peritonitis (SBPPr) in patients with cirrhosis has been considered the standard of care since the 1990s and is currently recommended by several major gastroenterological societies. However, the evidence that supports this practice is weak, and there is no clear mortality benefit. The unintended consequences of this strategy are not insignificant, both at the patient and population levels. Recent evidence suggests that SBPPr may even cause harm. Since the widespread implementation of SBPPr 3 decades ago, our overall approach to antibiotic use has shifted. We now recognize the growing threat of antimicrobial resistance, the potential harms of antibiotics, and the vital role of antimicrobial stewardship. In light of recent developments and evidence, there is an urgent need for infectious diseases, antimicrobial stewardship, and hepatology leaders to collaborate in development of an updated and cohesive approach to SBPPr.
Spontaneous bacterial peritonitis (SBP) is the most devastating infectious complication among persons living with cirrhosis, often triggering a cascade of organ dysfunction associated with mortality as high as 40% [1]. Patients with cirrhosis are at increased risk of infection due to several endogenous factors including impaired humoral and cell-mediated immunity, weakened gut mucosal barrier, and gut microbial alterations with a shift toward pathobionts [2–4]. Additionally, exogenous factors such as healthcare exposure and alcohol use further contribute to risk for infection (Figure 1) [2]. In an attempt to offset these risks and reduce episodes of SBP, antibiotic prophylaxis for SBP (SBPPr) has been recommended since the 1990s [5]. This strategy may be initiated after the first episode of SBP (secondary prophylaxis) or, in exceptionally high-risk patients, before the first episode of SBP (primary prophylaxis) and is continued for life or until liver transplant (Table 1) [6]. SBPPr is also recommended during acute upper gastrointestinal hemorrhage; however, this is short-lived and less problematic. In contrast, the use of lifelong fluoroquinolones (FQs) for SBPPr, whether primary or secondary, has become increasingly controversial. Several studies have challenged the effectiveness of this strategy and exposed its potential to induce antimicrobial resistance (AMR) and other harms [7–9]. Furthermore, the global landscape has shifted dramatically, recognizing the urgent threat of AMR and the need for robust action to curtail it [10, 11]. The new antibiotic mantra “shorter is better” [12] contrasts sharply with the practice of prescribing lifelong SBPPr in the absence of strong evidence. As concerns accumulate, it begs the question: Is it time to rethink our approach to antibiotic prophylaxis for SBP?
Factors that drive increased infection risk in cirrhosis. Image Source: National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health. Abbreviation: SBP, spontaneous bacterial peritonitis.
Current Consensus Guidance for Spontaneous Bacterial Peritonitis Prophylaxis and Suggested Modifications
| Strategy | Criteria | Antibiotic Agent | Duration | Suggested Modifications |
|---|---|---|---|---|
| Primary prophylaxis (for prevention of first episode of SBP) | Cirrhosis and acute upper gastrointestinal hemorrhage | Ceftriaxone 1 g intravenous every 24 h for maximum of 7 d | 7 d maximum | None; this should be continued as recommended |
| Consider in patients with advanced cirrhosis (Child–Pugh score ≥9 and serum bilirubin ≥3 mg/dL) and low ascites protein (<1.5 g/dL) with either: impaired renal function (serum creatinine ≥1.2 mg/dL or blood urea nitrogen ≥25 mg/dL) or hyponatremia (serum sodium ≤130 mmol/L) | Norfloxacin 400 mg daily or Ciprofloxacin 500 mg daily or Trimethoprim-sulfamethoxazole 1 double-strength tablet daily Until liver transplantation or death | Until liver transplant or death | Cease to advise primary prophylaxis based on weakness of supporting evidence and risk for AMR, Clostridioides difficile infection, and other harms | |
| Secondary prophylaxis (for prevention of recurrent episodes of SBP) | Cirrhosis (any severity) and a first episode of SBP | Norfloxacin 400 mg daily or Ciprofloxacin 500 mg daily or Trimethoprim-sulfamethoxazole 1 double-strength tablet daily Until liver transplantation or death | Until liver transplant or death | Only recommend on a case-by-case basis with careful individual analysis of benefit versus risk Emphasize patient-centered decision-making Updated, larger, randomized, controlled trials are needed in context of current state of AMR and potential for harm |
| Strategy | Criteria | Antibiotic Agent | Duration | Suggested Modifications |
|---|---|---|---|---|
| Primary prophylaxis (for prevention of first episode of SBP) | Cirrhosis and acute upper gastrointestinal hemorrhage | Ceftriaxone 1 g intravenous every 24 h for maximum of 7 d | 7 d maximum | None; this should be continued as recommended |
| Consider in patients with advanced cirrhosis (Child–Pugh score ≥9 and serum bilirubin ≥3 mg/dL) and low ascites protein (<1.5 g/dL) with either: impaired renal function (serum creatinine ≥1.2 mg/dL or blood urea nitrogen ≥25 mg/dL) or hyponatremia (serum sodium ≤130 mmol/L) | Norfloxacin 400 mg daily or Ciprofloxacin 500 mg daily or Trimethoprim-sulfamethoxazole 1 double-strength tablet daily Until liver transplantation or death | Until liver transplant or death | Cease to advise primary prophylaxis based on weakness of supporting evidence and risk for AMR, Clostridioides difficile infection, and other harms | |
| Secondary prophylaxis (for prevention of recurrent episodes of SBP) | Cirrhosis (any severity) and a first episode of SBP | Norfloxacin 400 mg daily or Ciprofloxacin 500 mg daily or Trimethoprim-sulfamethoxazole 1 double-strength tablet daily Until liver transplantation or death | Until liver transplant or death | Only recommend on a case-by-case basis with careful individual analysis of benefit versus risk Emphasize patient-centered decision-making Updated, larger, randomized, controlled trials are needed in context of current state of AMR and potential for harm |
Abbreviations: AMR, antimicrobial resistance; SBP, spontaneous bacterial peritonitis.
Adapted from [6].
Current Consensus Guidance for Spontaneous Bacterial Peritonitis Prophylaxis and Suggested Modifications
| Strategy | Criteria | Antibiotic Agent | Duration | Suggested Modifications |
|---|---|---|---|---|
| Primary prophylaxis (for prevention of first episode of SBP) | Cirrhosis and acute upper gastrointestinal hemorrhage | Ceftriaxone 1 g intravenous every 24 h for maximum of 7 d | 7 d maximum | None; this should be continued as recommended |
| Consider in patients with advanced cirrhosis (Child–Pugh score ≥9 and serum bilirubin ≥3 mg/dL) and low ascites protein (<1.5 g/dL) with either: impaired renal function (serum creatinine ≥1.2 mg/dL or blood urea nitrogen ≥25 mg/dL) or hyponatremia (serum sodium ≤130 mmol/L) | Norfloxacin 400 mg daily or Ciprofloxacin 500 mg daily or Trimethoprim-sulfamethoxazole 1 double-strength tablet daily Until liver transplantation or death | Until liver transplant or death | Cease to advise primary prophylaxis based on weakness of supporting evidence and risk for AMR, Clostridioides difficile infection, and other harms | |
| Secondary prophylaxis (for prevention of recurrent episodes of SBP) | Cirrhosis (any severity) and a first episode of SBP | Norfloxacin 400 mg daily or Ciprofloxacin 500 mg daily or Trimethoprim-sulfamethoxazole 1 double-strength tablet daily Until liver transplantation or death | Until liver transplant or death | Only recommend on a case-by-case basis with careful individual analysis of benefit versus risk Emphasize patient-centered decision-making Updated, larger, randomized, controlled trials are needed in context of current state of AMR and potential for harm |
| Strategy | Criteria | Antibiotic Agent | Duration | Suggested Modifications |
|---|---|---|---|---|
| Primary prophylaxis (for prevention of first episode of SBP) | Cirrhosis and acute upper gastrointestinal hemorrhage | Ceftriaxone 1 g intravenous every 24 h for maximum of 7 d | 7 d maximum | None; this should be continued as recommended |
| Consider in patients with advanced cirrhosis (Child–Pugh score ≥9 and serum bilirubin ≥3 mg/dL) and low ascites protein (<1.5 g/dL) with either: impaired renal function (serum creatinine ≥1.2 mg/dL or blood urea nitrogen ≥25 mg/dL) or hyponatremia (serum sodium ≤130 mmol/L) | Norfloxacin 400 mg daily or Ciprofloxacin 500 mg daily or Trimethoprim-sulfamethoxazole 1 double-strength tablet daily Until liver transplantation or death | Until liver transplant or death | Cease to advise primary prophylaxis based on weakness of supporting evidence and risk for AMR, Clostridioides difficile infection, and other harms | |
| Secondary prophylaxis (for prevention of recurrent episodes of SBP) | Cirrhosis (any severity) and a first episode of SBP | Norfloxacin 400 mg daily or Ciprofloxacin 500 mg daily or Trimethoprim-sulfamethoxazole 1 double-strength tablet daily Until liver transplantation or death | Until liver transplant or death | Only recommend on a case-by-case basis with careful individual analysis of benefit versus risk Emphasize patient-centered decision-making Updated, larger, randomized, controlled trials are needed in context of current state of AMR and potential for harm |
Abbreviations: AMR, antimicrobial resistance; SBP, spontaneous bacterial peritonitis.
Adapted from [6].
LOW-QUALITY EVIDENCE DRIVING PRACTICE
The seminal study supporting secondary prophylaxis for SBP was published in 1990 by Ginés et al [5]. This double-blind, placebo-controlled trial included 80 patients (40 patients in each group). Participants in the intervention arm received norfloxacin 400 mg/d and were evaluated for SBP recurrence at 6 and 12 months. While there was a statistically significant reduction in recurrence of SBP, the study was underpowered to detect a difference in mortality, and there was no reduction in total incidence of infections. The results of this trial have been so widely accepted that no subsequent randomized, controlled trials (RCTs) have been published that exclusively evaluated the effectiveness of secondary prophylaxis versus placebo for the prevention of SBP [13]. Several SBPPr studies with mixed populations and antibiotic regimens have been performed since the 1990s, all with relatively small sample sizes. In 2020, a Cochrane review compared the benefits and harms of various antibiotic regimens for SBPPr (both primary and secondary) [9]. The study reviewed 29 RCTs and included 23, noting that the seminal study by Ginés et al was funded by an industrial organization who could benefit from the results of the study, and had unclear risk of incomplete outcome data bias, sequence generation bias, and allocation concealment bias [9]. Using aggregate data from the remaining 2587 participants across high-quality studies, no mortality benefit was identified, regardless of whether prophylaxis was primary or secondary. The authors concluded that “there is considerable uncertainty about whether antibiotic prophylaxis is beneficial, and if beneficial, which antibiotic prophylaxis is most beneficial” [9]. Despite these limitations, the study by Ginés et al still serves as the backbone of evidence to support the clinical effectiveness of SBPPr [6]. The current practice guidance from the American Association for the Study of Liver Diseases (AASLD) recommends initiating long-term secondary prophylaxis for SBP with norfloxacin and considering primary prophylaxis in high-risk cases (Table 1) [6]. Notably, norfloxacin is unique among FQs due to its poor oral bioavailability and high gut luminal concentrations; however, it was removed from the US market in 2014.
POTENTIAL HARMS ASSOCIATED WITH SBPPr
Antimicrobial-Resistant Infections in Patients With Cirrhosis
We face a global crisis of AMR causing 2.8 million antimicrobial-resistant infections and 35 000 deaths per annum in the United States alone [14]. It is well established that antibiotic exposure is the primary driver of this crisis, raising significant concerns about any strategy that involves placing patients on lifelong antibiotics. Not surprisingly, resistant infections are on the rise among patients with cirrhosis, occurring in 34% of cases globally [15]. When resistant infections occur in patients with multifactorial immune dysfunction, such as those with cirrhosis, outcomes can be severe, with mortality approaching 30% [15]. Patients who receive SBPPr with FQs develop progressively worsening multidrug-resistant organism colonization, including carbapenem-resistant Enterobacteriales, over time [16]. Moreover, patients are not exempt from developing SBP despite prophylaxis. When they do, infections are often multidrug-resistant and outcomes are worse [16].
We conducted a large cohort study of more than 7000 patients with cirrhosis within the Veterans Health Administration (VHA) and found that patients who received primary prophylaxis for SBP were 2.43 times (95% confidence interval, 1.63–3.60) more likely to have an FQ-resistant organism causing their first episode of SBP. Additionally, they had a greater length of stay (P < .01) compared with those not on SBPPr [7]. In another population-based study using VHA and TriNetX databases, secondary prophylaxis was associated with a 60% increased risk of SBP recurrence compared with those who were not started on prophylaxis, and this disparity worsened from 2005 to 2019 [8]. We again observed a higher prevalence of resistant organisms among patients on secondary prophylaxis; however, the overall yield was low due to the infrequent collection of peritoneal fluid cultures [8]. Additional studies are needed to confirm these findings and identify the underlying drivers of this phenomenon, although alterations in the gut microbiota and worsening AMR are likely contributing factors.
Antibiotic Side Effects and Clostridioides difficile
The first-line recommended agent for SBPPr remains an FQ [6]. Since publication of the initial SBP studies, the US Food and Drug Administration has issued a series of black box warnings on FQs for side effects that include tendon rupture, peripheral neuropathy, mental health issues, hypoglycemia, aortic aneurysm rupture, and dissection [17–19]. FQs are also associated with an increased risk of developing Clostridioides difficile infection (CDI) and range from 2 fold to 12.7 fold. However, all recommended agents for SBPPr are associated with increased risk of CDI [20]. We must recall that CDI is still considered an “urgent threat” by the Centers for Disease Control and Prevention, causing more than 200 000 cases and 12 000 deaths per annum in the United States [14]. Morbidity and mortality from CDI can be particularly high in patients with cirrhosis [21]. Given our current understanding of FQ side effects and their potential to cause harm, it is unlikely that a study that involves lifelong prophylactic courses of FQs would be approved by an institutional review board in the modern era. The most common alternative option for SBPPr is trimethoprim-sulfamethoxazole. While this agent is associated with a lower risk for CDI, hyperkalemia, acute kidney injury, hepatotoxicity, and cytopenias are well documented and may be severe in patients with cirrhosis [22].
Gut Microbial Alterations
More recently, gut microbial alterations and a shift toward pathobionts in the microbiota are thought to play a substantial role in gut mucosal breakdown and infectious complications in patients with cirrhosis. A healthy gut microbiome is an important component of the multilayered gut barrier. Microbial function, including endotoxin production, antibiotic resistance genes, and virulence factor expression, is disrupted in patients with decompensated cirrhosis and is associated with impaired local immune response in patients with SBP [23–26]. Moreover, nonbacterial kingdoms such as fungi and phages are also affected in patients on SBPPr, further amplifying the potential unintended consequences of antibiotic exposure [27]. Consequently, SBPPr may paradoxically increase the risk of gut translocation and the incidence of SBP over time.
A PATH FORWARD: FIRST, DO NO HARM
Many unanswered questions remain surrounding the effectiveness, optimal agent, duration, and unintended consequences of SBPPr (Table 2). While data that support secondary prophylaxis are more convincing than data that support primary prophylaxis, the current evidence for either strategy is of poor quality and in need of larger, updated RCTs with better methodology. Moving forward, we must rethink our approach to SBPPr and carefully consider whether the benefits truly outweigh the risks.
Unanswered Questions Surrounding Spontaneous Bacterial Peritonitis Prophylaxis in Patients With Cirrhosis
| Is there a mortality benefit to providing SBPPr (whether primary or secondary)? |
| In the setting of escalating rates of antimicrobial resistance among patients with cirrhosis, is SBPPr still as effective as it was presumed to be in the 1990s? |
| In patients with a history of fluoroquinolone- or trimethoprim-sulfamethoxazole–resistant infections, is SBPPr still effective? |
| In the setting of unavailability of norfloxacin, which antibiotic is most effective for the prevention of SBP? |
| Are there specific subpopulations of patients with cirrhosis (eg, primary prophylaxis, secondary prophylaxis, awaiting transplantation) who derive greater benefit from SBPPr? |
| Should SBPPr be continued in patients who develop breakthrough SBP despite receiving SBPPr? |
| What is the ideal duration of SBPPr in patients with cirrhosis? When should SBPPr be discontinued? |
| What is the role of fecal microbiota transplant and phage therapy in the prevention of spontaneous bacterial peritonitis? |
| Is there a mortality benefit to providing SBPPr (whether primary or secondary)? |
| In the setting of escalating rates of antimicrobial resistance among patients with cirrhosis, is SBPPr still as effective as it was presumed to be in the 1990s? |
| In patients with a history of fluoroquinolone- or trimethoprim-sulfamethoxazole–resistant infections, is SBPPr still effective? |
| In the setting of unavailability of norfloxacin, which antibiotic is most effective for the prevention of SBP? |
| Are there specific subpopulations of patients with cirrhosis (eg, primary prophylaxis, secondary prophylaxis, awaiting transplantation) who derive greater benefit from SBPPr? |
| Should SBPPr be continued in patients who develop breakthrough SBP despite receiving SBPPr? |
| What is the ideal duration of SBPPr in patients with cirrhosis? When should SBPPr be discontinued? |
| What is the role of fecal microbiota transplant and phage therapy in the prevention of spontaneous bacterial peritonitis? |
Abbreviation: SBPPr, spontaneous bacterial peritonitis prophylaxis.
Unanswered Questions Surrounding Spontaneous Bacterial Peritonitis Prophylaxis in Patients With Cirrhosis
| Is there a mortality benefit to providing SBPPr (whether primary or secondary)? |
| In the setting of escalating rates of antimicrobial resistance among patients with cirrhosis, is SBPPr still as effective as it was presumed to be in the 1990s? |
| In patients with a history of fluoroquinolone- or trimethoprim-sulfamethoxazole–resistant infections, is SBPPr still effective? |
| In the setting of unavailability of norfloxacin, which antibiotic is most effective for the prevention of SBP? |
| Are there specific subpopulations of patients with cirrhosis (eg, primary prophylaxis, secondary prophylaxis, awaiting transplantation) who derive greater benefit from SBPPr? |
| Should SBPPr be continued in patients who develop breakthrough SBP despite receiving SBPPr? |
| What is the ideal duration of SBPPr in patients with cirrhosis? When should SBPPr be discontinued? |
| What is the role of fecal microbiota transplant and phage therapy in the prevention of spontaneous bacterial peritonitis? |
| Is there a mortality benefit to providing SBPPr (whether primary or secondary)? |
| In the setting of escalating rates of antimicrobial resistance among patients with cirrhosis, is SBPPr still as effective as it was presumed to be in the 1990s? |
| In patients with a history of fluoroquinolone- or trimethoprim-sulfamethoxazole–resistant infections, is SBPPr still effective? |
| In the setting of unavailability of norfloxacin, which antibiotic is most effective for the prevention of SBP? |
| Are there specific subpopulations of patients with cirrhosis (eg, primary prophylaxis, secondary prophylaxis, awaiting transplantation) who derive greater benefit from SBPPr? |
| Should SBPPr be continued in patients who develop breakthrough SBP despite receiving SBPPr? |
| What is the ideal duration of SBPPr in patients with cirrhosis? When should SBPPr be discontinued? |
| What is the role of fecal microbiota transplant and phage therapy in the prevention of spontaneous bacterial peritonitis? |
Abbreviation: SBPPr, spontaneous bacterial peritonitis prophylaxis.
In our opinion, pending more convincing evidence, the decision to proceed with SBPPr, whether primary or secondary, should be generally discouraged and highly individualized. This approach aligns with the bioethical principle of “primum non nocere” —first, do no harm—that, when considered alongside accumulating evidence, does not support lifelong SBPPr.
The existing guidance statements from the AASLD, especially regarding secondary prophylaxis, along with additional data, could be modified to allow for greater individualization and acknowledgment of research gaps (Table 1).
While we await updated consensus guidance, antimicrobial stewardship programs should prioritize working with gastrointestinal/hepatology colleagues to develop local SBPPr guidance that incorporates the above perspectives. Shared decision-making with patients should also be emphasized, as patients often have a limited understanding of antibiotic risks [28]. Our recommendations place high value on the importance of preventing the development and spread of AMR, C. difficile, gut microbial alterations, and antibiotic side effects. We eagerly await the results of the ASEPTIC trial, a multicenter RCT designed to assess the effectiveness of primary SBPPr and adequately powered to determine if a mortality benefit exists [29]. Collaboration among hepatology, infectious diseases, and antimicrobial stewardship leaders is urgently needed to shape future strategies to prevent SBP.
Notes
Financial support. Veterans Affairs Merit Award I01CX002472 and 2I01CX001076 to J. S. B.
References
Author notes
Potential conflicts of interest. The authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest.
