Increasing Concerns Surrounding Prevalence of Infections in Cirrhosis

The natural history of cirrhosis is significantly affected by the increasing prevalence of infections, thought to be caused by concomitant medications and indiscriminate use of antibiotics resulting in radical changes in the virulence of causative organisms. This, according to a review published in The New England Journal of Medicine. The review authors also highlighted the importance of a high index of suspicion, early diagnosis, rapid administration of effective antibiotics, and the prevention of multiorgan failure to improve survival outcomes in this patient population. 

“Despite the increasing prevalence of infections among patients with cirrhosis, developing strategies for prevention, early detection, and treatment has been challenging,” the review authors noted.

The pathogenesis of infection in patients with cirrhosis is the result of inherent and external factors that synergistically exacerbate infection. Some major internal factors include cirrhosis-associated immune dysfunction, reduction in bile flow, and changes in gut microbiota and associated functions. Some external factors include the overuse of proton-pump inhibitors, alcohol consumption, frailty, multiple antibiotic courses, repeated hospital admissions, and invasive procedures.

The most common infections in patients with cirrhosis include spontaneous bacterial peritonitis, urinary tract infection, pneumonia, spontaneous bacteremia, skin and soft tissue infections, and Clostridioides difficile infection. In addition to bacterial infections, fungal infections can occur in 10% to 13% of patients with cirrhosis, and bacterial and fungal coinfections can significantly reduce survival rates compared with bacterial infections alone.

In patients presumed to have infection who have negative bacterial cultures, especially those with renal insufficiency and those on multiple antibiotic courses, fungal infections should be suspected. Febrile response may vary, as patients with decompensated cirrhosis may not have fever; therefore, a new onset of acute kidney injury, altered mental status, or signs of organ failure, fever, and leukocytosis warrant an investigation for infections. While C-reactive protein and procalcitonin levels are often elevated in this patient population, regardless of infection, a persistent elevation in C-reactive protein may be indicative of short-term risk for death.

Spontaneous bacterial peritonitis can occur in 23% to 27% of patients, with a 90-day mortality rate ranging from 13% to 41%. Risk factors for spontaneous bacterial peritonitis include advanced cirrhosis, gastrointestinal bleeding, and previous spontaneous bacterial peritonitis. The most common organisms causing these types of infections include Escherichia coli (E coli), Klebsiella pneumoniae (K pneumoniae), Streptococcus pneumonia (S pneumonia), and Streptococcus viridans (S viridans).

The first line of therapy for patients with community-acquired infection is intravenous (IV) third-generation cephalosporins such as cefotaxime or ceftriaxone. Other therapeutic interventions include IV ciprofloxacin or oral ofloxacin, and piperacillin-tazobactam is recommended in countries with high bacterial resistance.

Urinary tract infections, largely due to E coli, K pneumoniae, enterococcus species, and Pseudomonas aeruginosa, are prevalent in 22% to 29% of patients and result in 90-day overall mortality in 19% of patients. In uncomplicated infection, oral quinolones or trimethoprim-sulfamethoxazole may be used; however, in the case of sepsis, IV third-generation cephalosporins or piperacillin-tazobactam is suggested.

As urinary catheterization is a risk factor for urinary tract infections in patients with cirrhosis, avoiding unnecessary catheterization, removing the catheter as soon as it is no longer required, and following infection prevention polices are some ways to prevent infection. Unless clinically indicated, prophylaxis with antimicrobial agents is not recommended. 

There is a 19% prevalence of pneumonia is patients with cirrhosis, namely due to S pneumoniae, gram-negative bacilli, and staphylococci; 25% of patients have a 90-day overall mortality. Risk factors include ventilator use and previous antibiotic therapy, while prophylaxis includes pneumococcal vaccination.

Therapeutic interventions for patients with cirrhosis who have community-acquired pneumonia include ceftriaxone plus macrolide, piperacillin–tazobactam, levofloxacin, and moxifloxacin. For aspiration pneumonia, the use of levofloxacin plus metronidazole is recommended.

Spontaneous bacteremia, caused mainly by E coli, S viridans, and other streptococcus species, occurs in 8% to 13% of patients with cirrhosis, resulting in a 33% 90-day overall mortality. In patients who are hemodynamically unstable, piperacillin-tazobactam is preferred. For patients who are hemodynamically stable, cefotaxime, ceftriaxone, or amoxicillin-clavulanic acid is recommended.

Fungal infections, especially candidiasis caused by Candida albicans or other candida species, are prevalent in 5% to 10% of patients with cirrhosis and result in worse survival outcomes with bacterial coinfection. Risk factors for fungal infections include impaired renal function, health care-associated or nosocomial settings, and alcohol-associated cirrhosis on glucocorticoid therapy for alcohol-associated hepatitis. In addition, there is a higher incidence of fungal infection among women.

Prophylaxis may include fluconazole or liposomal amphotericin B to reduce invasive fungal infections in liver transplant recipients. For community-acquired infections, echinocandins such as IV caspofungin, micafungin, or anidulafungin are recommended. However, testing for echinocandin susceptibility should be considered in patients who have previously been treated with echinocandin and for patients who have Candida glabrata or Candida parapsilosis infection.

“Management of infections in patients with cirrhosis requires, first, identification of the causative organism, including fungal pathogens; second, prevention of multiorgan failure; third, avoidance of nosocomial infections; and finally, determination of the prognosis,” the authors noted. “In addition, management entails decisions about referring patients for critical care evaluation, liver transplantation, and end-of-life care.”

The current approach for infection in patients with cirrhosis is the administration of antibiotics. Although antibiotic use is highly effective when the causative organism and sensitivities are identified, drug resistance and antibiotic overuse are challenging and limit the strength of this therapy option.

While prebiotics may impair pathogen growth via production of new glycans, they are ineffective as standalone agents and do not have enough supporting evidence to be recommended for clinical use. Probiotics themselves can lead to infections and have had low efficacy in recent trials.

Fecal microbiota transplantation has been effective for C difficile infections and the number of multidrug-resistant organisms and antibiotic-resistant bacteria have been found to be low after transplantation. While fecal microbiota transplantation is safe in patients with cirrhosis, antibiotics must be avoided and the mode of delivery and dose is still unclear.

“Prevention of further infections and the negative effects of infections on liver transplantation candidacy remain challenges. Effective management strategies are urgently required to improve the poor prognosis for patients with cirrhosis who have infections,” the investigators concluded.

Disclosure: Multiple authors declared affiliations with industry. Please refer to the original article for a full list of disclosures.

Reference

Bajaj JS, Kamath PS, Reddy KR. The evolving challenge of infections in cirrhosis. N Engl J Med. 2021;384(24):2317-2330. doi:10.1056/NEJMra2021808