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Prophylaxis of spontaneous bacterial peritonitis: Is there still room for quinolones?

Published:February 01, 2019DOI:https://doi.org/10.1016/j.jhep.2018.12.032

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      • EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis
        Journal of HepatologyVol. 69Issue 2
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          The natural history of cirrhosis is characterised by an asymptomatic compensated phase followed by a decompensated phase, marked by the development of overt clinical signs, the most frequent of which are ascites, bleeding, encephalopathy, and jaundice. The following Clinical Practice Guidelines (CPGs) represent the first CPGs on the management of decompensated cirrhosis. In this context, the panel of experts, having emphasised the importance of initiating aetiologic treatment for any degree of hepatic disease at the earliest possible stage, extended its work to all the complications of cirrhosis, which had not been covered by the European Association for the Study of the Liver guidelines, namely: ascites, refractory ascites, hyponatremia, gastrointestinal bleeding, bacterial infections, acute kidney injury, hepatorenal syndrome, acute-on-chronic liver failure, relative adrenal failure, cirrhotic cardiomyopathy, hepatopulmonary syndrome, and porto-pulmonary hypertension.
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      • Reply to: “Prophylaxis of spontaneous bacterial peritonitis: is there still room for quinolones?”
        Journal of HepatologyVol. 70Issue 5
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          We read with great interest the Letter by Lombardi et al. on “Prophylaxis of spontaneous bacterial peritonitis: Is there still room for quinolones?” First, we would like to offer a few words of sincere gratitude for the kind words that the authors used in evaluating the European Association for the Study of the Liver (EASL) Clinical Practice Guidelines (CPGs) that we recently had the burden and the honor of publishing.1
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      To the Editor:
      As members we are really proud of the recently published Association’s Clinical Practice Guidelines (CPGs) for the management of patients with decompensated cirrhosis.
      • Angeli P.
      • Bernardi M.
      • Villanueva C.
      • Francoz C.
      • Mookerjee R.P.
      • Trebicka J.
      • et al.
      EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis.
      They offer a precise and careful dissection of the issues encountered during the management of these delicate patients and provide clear and justified indications for treatment.
      Especially relevant for us are the indications provided about prophylaxis of spontaneous bacterial peritonitis (SBP). The CPGs suggest that antibiotic prophylaxis should be performed in 3 high-risk patient populations: patients with acute gastrointestinal (GI) haemorrhage, patients with low total protein content in ascitic fluid and no prior history of SBP (primary prophylaxis) and patients with a previous history of SBP (secondary prophylaxis). Whereas ceftriaxone is the antibiotic of choice in those with GI haemorrhage, norfloxacin, a molecule belonging to the class of fluoroquinolone antibiotics, is recommended for both primary and secondary prophylaxis. Norfloxacin administration must be continued until long-lasting improvement of clinical condition and disappearance of ascites in patients undergoing primary prophylaxis whilst is unclear if it can be interrupted in those receiving secondary prophylaxis. It must be noted that the American Association for the Study of Liver Disease (AASLD) Guidelines for the management of adult patients with ascites due to cirrhosis suggest a similar approach. Indeed, patients who have survived an episode of SBP should receive long-term prophylaxis with daily norfloxacin.
      • Runyon B.A.
      AASLD practice guideline management of adult patients with ascites due to cirrhosis: update 2012.
      The rationale behind the administration of fluoroquinolones in cirrhotic patients is to reduce the translocation of gram-negative bacteria from the gut lumen, as these bacteria are responsible for SBP in the majority of cases. The use of other molecules such as rifaximin, poorly absorbed in the gastrointestinal tract with high intraluminal levels, is a promising alternative but lacks sufficient evidence for use and has not been endorsed by scientific associations.
      • Goel A.
      • Rahim U.
      • Nguyen L.H.
      • Nguyen M.H.
      Rifaximin for the prophylaxis of spontaneous bacterial peritonitis: a meta-analysis.
      On the 16th of November the European Medicines Agency (EMA) released a review on quinolone and fluoroquinolone antibiotics, recommending a restriction in these drugs use due to the possible side effects: tendonitis, tendon rupture, arthralgia, pain in extremities, gait disturbance, neuropathies associated with paraesthesia, depression, fatigue, memory impairment, sleep disorders, and impaired hearing, vision, taste and smell.

      European Medicine Agency (EMA/795349/2018), Disabling and potentially permanent side effects lead to suspension or restrictions of quinolone and fluoroquinolone antibiotics. 2018.

      The EMA document was preceded by multiple Food and Drug Administration (FDA) Drug Safety Communications suggesting that fluoroquinolone antibiotics may cause significant decreases in blood sugar and certain mental health side effects (07-10-2018), may lead to side effects involving the tendons, muscles, joints, nerves, and central nervous system (05-12-2016), may cause peripheral neuropathy (08-15-2013) and are associated with an increased risk of developing tendonitis and tendon rupture (Boxed Warning, 07-08-2008). Moreover, mounting evidence suggests an increased incidence of aortic aneurysm or dissection associated with use of oral fluoroquinolones.
      • Lee C.C.
      • Gabriel Lee M.T.
      • Chen Y.S.
      • Lee S.H.
      • Chen Y.S.
      • Chen S.C.
      • et al.
      Risk of aortic dissection and aortic aneurysm in patients taking oral fluoroquinolone.
      • Lee C.C.
      • Lee M.G.
      • Hsieh R.
      • Porta L.
      • Lee W.C.
      • Lee S.H.
      • et al.
      Oral fluoroquinolone and the risk of aortic dissection.
      • Pasternak B.
      • Inghammar M.
      • Svanström H.
      Fluoroquinolone use and risk of aortic aneurysm and dissection: nationwide cohort study.
      Uncertainties about fluoroquinolone use are not only limited to side effects, important concerns about bacterial resistance are arising. Based on the latest Annual report of the European Antimicrobial Resistance Surveillance Network (EARS-Net), in Europe 22.8% of Escherichia coli isolates and 29.7% of Klebsiella pneumoniae isolates were resistant to fluoroquinolones in 2015, with relevant geographical discrepancies.

      European Centre for Disease Prevention and Control (ECDC). Antimicrobial resistance surveillance in Europe 2015. 2016.

      It means that already at beginning of treatment, SBP with quinolones is ineffective in about one-fifth to one-third of patients. Without taking into account the fact that cirrhotic patients are experienced to health care structures, and thus carry a higher probability of being colonized by multidrug resistant germs. Furthermore, fluoroquinolone exposure increases the rate of resistant microorganism isolation beside the enteric microbiota. Tacconelli et al.
      • Tacconelli E.
      • De angelis G.
      • Cataldo M.A.
      • Pozzi E.
      • Cauda R.
      Does antibiotic exposure increase the risk of methicillin-resistant Staphylococcus aureus (MRSA) isolation? A systematic review and meta-analysis.
      showed that quinolone use was associated with a risk ratio of 3 of acquiring methicillin-resistant Staphylococcus aureus (MRSA) infection, the highest across different class of antibiotics, with relevant consequences in infections other than SBP.
      Taken together, all these data suggest that we have to rethink the use of quinolones and fluoroquinolones for SBP prophylaxis. Despite the laudable service rendered, evidence is shifting the balance toward a prevalence of negative consequences. If we want to continue to use these drugs for SBP prophylaxis, proof showing their impact on both side effects and antimicrobial resistance in this specific setting are demanded. Moreover, also in this setting, antibiotic stewardship programmes should be implemented: they consist of a series of policies aimed at the appropriate use of antimicrobial drugs in order to reduce microbial resistance and decrease the spread of multidrug resistant organisms.
      • Zuccaro V.
      • Columpsi P.
      • Sacchi P.
      • Lucà M.G.
      • Fagiuoli S.
      • Bruno R.
      Antibiotic stewardship and empirical antibiotic treatment: how can they get along?.
      Otherwise, alternative/new regimens must be sought: in the meantime, prophylaxis with trimethoprim/sulfamethoxazole can be considered a safe and effective alternative and it has already been endorsed by AASLD guidelines. Rifaximin, with its peculiar pharmacokinetic properties limiting the systemic values of the drug, and thus the side effects, is a promising alternative. However, larger and well-conducted randomised controlled trials are needed to establish the non-inferiority of rifaximin compared to systemic antibiotics for SBP prophylaxis.

      Financial support

      The authors received no financial support to produce this manuscript.

      Conflict of interest

      The authors declare no conflicts of interest that pertain to this work.
      Please refer to the accompanying ICMJE disclosure forms for further details.

      Supplementary data

      The following are the Supplementary data to this article:

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