CME Author: Zeena Nackerdien
Study Authors: Salvatore Piano, Virendra Singh, et al.
Target Audience and Goal Statement: Infectious Disease Specialists, Gastroenterologists, Hospitalists, and Primary Care Physicians
The goal was to explore results from a multicenter prospective intercontinental study that assessed the prevalence and outcomes of bacterial and fungal infections in hospitalized patients with cirrhosis.
Members of the International Club of Ascites Global Study Group addressed the following questions:
- What was the worldwide epidemiology of microbial (bacterial and fungal) infections in hospitalized patients with cirrhosis?
- What was the clinical consequences of these infected patients following empirical administration of antibiotics?
Synopsis and Perspective:
Patients with cirrhosis – the late stage of progressive hepatic fibrosis characterized by distortion of the hepatic architecture and formation of regenerative nodules – are susceptible to an array of complications and have shortened life expectancies. While the risk of death from major complications of cirrhosis, such as hepatorenal syndrome, gastrointestinal bleeding, or hepatocellular carcinoma (HCC) has declined, the risk from sepsis has increased over time. Lack of new effective antibiotics and the spread of multidrug-resistant (MDR) bacteria have likely contributed to this phenomenon. Leaders of this study saw a need to strengthen the evidence base with respect to microbial infections, particularly MDR and extensively drug resistant (XDR) bacteria in hospitalized patients with cirrhosis.
From 2015 to 2016, demographic, clinical, and microbiological treatment data were collected by senior investigator Paolo Angeli, MD, PhD, of the University of Padua in Italy, and colleagues from 1,302 patients at 46 centers (15 from Asia, 15 from Europe, 11 from Southern America, and five from Northern America). The etiology of cirrhosis was different, with hepatitis B virus being more frequent in Asia than in Europe and America. Hepatitis C virus was more frequently associated with cirrhosis in the latter two regions.
Patients had advanced liver disease, as evidenced by a few key criteria: mean model of end stage liver disease (MELD) score (21±8); MELD sodium (MELD-Na) score (24±8); and a 35% rate of acute-on-chronic liver failure (ACLF) at the diagnosis of infection.
Just over 40% of the hospitalized patients with cirrhosis and bacterial or fungal infections were from Europe, 32% were from Asia, and 25% were from North or South America. Most of the patients were middle-age males (69%; mean age 57 years).
The primary outcome of the study was the prevalence of MDR or XDR infections. MDR bacteria were defined as not susceptible to at least one agent in three or more antimicrobial categories. XDR bacteria were defined as those susceptible to agents in no more than two categories. Intrinsic resistance was not considered for these definitions (e.g., Enterococci are constitutively resistant to cephalosporins). Secondary outcomes included in-hospital mortality, 28-day mortality, development of ACLF, septic shock, transfer to the intensive care unit, and need for organ support (mechanical ventilation or renal replacement therapy) during hospitalization.
The most frequent bacterial infections identified were spontaneous bacterial peritonitis (SBP, 27%), urinary tract infections (22%), and pneumonia (19%). Angeli and colleagues estimated that the global prevalence of MDR bacteria was 34% (95% CI 31%–37%). Indian and North American centers had the highest and lowest proportions of MDR and XDR bacteria, respectively (India: 73% and 33%, respectively; North America: 18% and 2%, respectively). Antibiotic use in the 3 months before hospitalization, prior health care exposure, and the site of infection were also identified as independent risk factors for MDR bacteria.
Prevalence of MDR and XDR bacteria across different geographical regions were further analyzed in 740 patients with positive cultures. Of the 959 bacteria isolated worldwide, most of the organisms were Gram-negative (57%) or Gram-positive (38%) and only 4% were fungi. The most commonly isolated MDR bacteria were extended-spectrum beta lactamase-producing Enterobacteriaceae, methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococci, Pseudomonas aeruginosa, and Acinetobacter baumannii. The proportion of patients with XDR bacteria was 8%.
Cirrhosis patients with MDR bacteria had a lower rate of response to empirical antibiotic treatment than patients with no MDR bacteria (40% vs 68%, P<0.001). Additional comparative data showed that infection with MDR bacteria was associated with:
- Lower rates of infection resolution (72% vs 82%, P=0.003)
- Higher incidence of septic shock during hospitalization (27% vs 13%, P<0.001)
- Higher in-hospital mortality (31% vs 21%, P=0.004)
On the other hand, an adequate empirical antibiotic treatment was independently associated with improved in-hospital and 28-day survival.
Study limitations included a lack of tools to test for specific genetic resistance and lack of inclusion of data from Africa.
Source Reference: Gastroenterology , Dec. 13, 2018, DOI: https://doi.org/10.1053/j.gastro.2018.12.005
Study Highlights: Explanation of Findings
This was the largest and the first global study to investigate the epidemiology and outcomes of bacterial infections in hospitalized patients with liver cirrhosis. Community-acquired infections outnumbered healthcare-associated or nosocomial infections in all the continents, especially Asia. However, almost 50% of patients acquired a bacterial infection after exposure to a healthcare facility.
Global prevalence of infections sustained by MDR bacteria was higher than prior reports, with the highest rates of MDR and XDR bacteria reported in India. Over-the-counter antibiotics and presence of the drugs in the environment were two reasons cited by the authors for their findings in India; however, they noted that “a significant proportion of the population lacks access to doctors and that a lack of access to effective antibiotics still kills more children than antibiotic resistance.”
While the other findings confirmed evidence from the literature, the most striking finding was a negative one. Unlike most previous reports, SBP prophylaxis with quinolones was not a predictor for infections with MDR bacteria. Angeli and colleagues hypothesized that environmental antibiotics potentially played a role; alternatively, the low proportion of patients who received quinolone prophylaxis (10%) could also account for discrepancies between the findings. But the current results were in keeping with a randomized clinical trial which showed that the risk of developing infections due to MDR bacteria was not higher in patients receiving a fluoroquinolone, norfloxacin, versus placebo. In the absence of an effective and safe alternative, the authors concluded that quinolones were viable options for the treatment of primary or secondary SBP.
“XDR bacteria were more difficult to treat and were associated with a high risk of lack of infection resolution, organ failures, septic shock, and, most remarkably, in-hospital and 28-day mortality,” the authors also noted.
Microbiological efficacy of empirical antibiotic treatment was a strong independent and the only potentially modifiable predictor of mortality beyond age, the degree of inflammation, MELD-Na, ACLF, and the new quick sequential organ failure assessment (qSOFA) score.
Marked geographical differences in the prevalence of infections with MDR and XDR bacteria illustrated the difficulties of developing standardized, worldwide antimicrobial stewardship programs. Instead, Angeli and colleagues favored adaptation of schemes to national, regional, or even local microbiological epidemiology. Additionally, active screening with nasal and rectal swabs in high-risk patients (those with a prior MDR isolate, those coming from another hospital/nursing home, or those being admitted to or discharged from the intensive care unit) could identify carriers of MDR bacteria, and contact precautions and hand hygiene may help prevent further spread of these organisms.
The 34% prevalence of MDR bacteria in the cirrhotic population should be a wake-up call, Scott L. Friedman, MD, of Icahn School of Medicine at Mount Sinai in New York City, who was not involved in the research, told MedPage Today. “This is a unique and comprehensive study that is unlikely to be replicated with this kind of rigor any time soon. It’s a warning that antibiotics have to be used judiciously and that the possibility of MDR should always be a consideration, particularly in those regions where it is more likely.”
“Antibiotic selection should be guided by identification of the bacteria,” Friedman added. He noted that while there is a high level of vigilance in the U.S., where standard care is based on microbial identification, it must be maintained and heightened in patients with cirrhosis since they are at greater risk of infection and are already immunocompromised.
Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco