Advertisement

Reply to: “Prophylaxis of spontaneous bacterial peritonitis: is there still room for quinolones?”

  • Paolo Angeli
    Correspondence
    Corresponding author. Address: Unit of Internal Medicine and Hepatology (UIMH), Dept. of Medicine (DIMED), University of Padova, Via Giustiniani 2, Padova cap. 35128, Italy. Tel.: +39 0498212291-2285.
    Affiliations
    Unit of Internal Medicine and Hepatology (UIMH), Dept. of Medicine (DIMED), University of Padova, Italy
    Search for articles by this author
  • Author Footnotes
    # On behalf of the European Association for the Study of the liver.
    Mauro Bernardi
    Footnotes
    # On behalf of the European Association for the Study of the liver.
    Affiliations
    Dept. of Medical and Surgical Sciences, Alma Mater Studiorum-University of Bologna, Italy
    Search for articles by this author
  • Author Footnotes
    # On behalf of the European Association for the Study of the liver.
Published:February 02, 2019DOI:https://doi.org/10.1016/j.jhep.2019.01.011

      Linked Article

      • EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis
        Journal of HepatologyVol. 69Issue 2
        • Preview
          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.
        • Full-Text
        • PDF
      • Prophylaxis of spontaneous bacterial peritonitis: Is there still room for quinolones?
        Journal of HepatologyVol. 70Issue 5
        • Preview
          As members we are really proud of the recently published Association’s Clinical Practice Guidelines (CPGs) for the management of patients with decompensated cirrhosis.1 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.
        • Full-Text
        • PDF
      To the Editor:
      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.
      • EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis
      That said, it is our wish to directly address the main comment of Lombardi et al. related to the use of norfloxacin in primary and secondary prophylaxis of spontaneous bacterial peritonitis (SBP) in patients with cirrhosis, which is the following: “data suggest that we have to rethink the use of quinolones and fluoroquinolones for SBP prophylaxis”. The authors based their conclusion on 3 main issues: a) the side effects of fluoroquinolones recently referred to by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA), b) the high resistance profile to fluoroquinolones and c) the contribution of fluoroquinolones in generating multidrug resistant (MDR) and extensively drug resistant (XDR) bacteria.
      Regarding the adverse effects, we would like to recall that some of them, that is those involving the osteo-muscular apparatus and the central and peripheral nervous system,

      Europen Medicines Agency. Disabling and potentially permanent side effects lead to suspension or restrictions of quinolone and fluoroquinolone antibiotics. 2018;44.

      have long been recognised while others, such as the possible hypoglycaemic effect of norfloxacin or its possible contributory role in the pathogenesis of aortic aneurysms, were only recently reported, after the publication of the CPGs.
      • 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.
      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.
      We do not intend to underestimate the relevance of the FDA and EMA documents mentioned by the authors, but it must be recognised that no report on the significant adverse effects of norfloxacin is currently available from randomised clinical trials (RCTs) or in studies of “real clinical practice” with norfloxacin as prophylaxis for SBP.
      Moving to the high resistance profile of isolates of Escherichia coli and Klebsiella pneumoniae to fluoroquinolones reported by the European Antimicrobial Resistance Surveillance Network in 2015,

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

      we agree with Lorenzi et al. that this problem opens the discussion on how to prevent a relapse of SBP when the index episode was sustained by a quinolone-resistant bacterium. Thus, we agree that alternative regimens must be sought and tested in RCTs, particularly in secondary prophylaxis of SBP, while, in the meantime, rifaximin could be used empirically.
      • Goel A.
      • Rahim U.
      • Nguyen L.H.
      • Stave C.
      • Nguyen M.H.
      Rifaximin for the prophylaxis of spontaneous bacterial peritonitis: a systematic review.
      But, we do not agree with the use of trimethoprim/sulfametoxazole in the prophylaxis of SBP, since it must be remembered that the prevalence of trimethoprim/sulfametoxazole-resistant microorganisms isolated from patients with cirrhosis is at least as high as that of quinolone-resistant strains.
      • Fernández J.
      • Navasa M.
      • Gómez J.
      • Colmenero J.
      • Vila J.
      • Arroyo V.
      • et al.
      Bacterial infections in cirrhosis: epidemiological changes with invasive procedures and norfloxacin prophylaxis.
      Nevertheless, we would like to point out that, even in the context of secondary prophylaxis, the problem of the resistance of gram-negative bacteria to quinolones is far more complex than it may appear. In fact, a) there are either some doubt on the invasive capacity of quinolone-resistant gram-negative bacteria,
      • Marciano S.
      • Dirchwolf M.
      • Diaz J.M.
      • Bermudez C.
      • Gutierrez-Acevedo M.N.
      • Barcán L.A.
      • et al.
      Spontaneous bacterial peritonitis recurrence in patients with cirrhosis receiving secondary prophylaxis with norfloxacin.
      or some evidence that sub-minimum inhibitory concentrations of norfloxacin are able to reduce the in vitro adherence on epithelial cells by E. Colistrains from patients with cirrhosis, a capability not affected by the resistance to quinolones;
      • Gascón I.
      • Pascual S.
      • Plazas J.
      • Sánchez J.
      • Francés R.
      • Más P.
      • et al.
      Norfloxacin decreases bacterial adherence of quinolone-resistant strains of Escherichia coli isolated from patients with cirrhosis.
      b) it is not known how long a quinolone-resistant strain of a gram-negative bacterium, responsible for an episode of SBP can maintain its profile of resistance in the microbiome of a patient with cirrhosis.
      All this makes it possible to explain why in a recent multicentre French RCT, long term norfloxacin prophylaxis was able to reduce the rate of infections sustained by gram-negative bacteria and improve survival in patients with Child-Pugh class C cirrhosis at high risk of developing SBP.
      • Moreau R.
      • Elkrief L.
      • Bureau C.
      • Perarnau J.M.
      • Thévenot T.
      • Saliba F.
      • et al.
      Effects of long-term norfloxacin therapy in patients with advanced cirrhosis.
      Finally let us comment on the potential role of prophylaxis of SBP with norfloxacin in the selection of MDR or XDR bacteria. This is a very common belief among hepatologists, but again not supported by the most recent data, that Lorenzi et al. did not mention. In fact, this belief was not confirmed by the French RCT previously quoted
      • Moreau R.
      • Elkrief L.
      • Bureau C.
      • Perarnau J.M.
      • Thévenot T.
      • Saliba F.
      • et al.
      Effects of long-term norfloxacin therapy in patients with advanced cirrhosis.
      and by the largest prospective, observational study conducted worldwide on the epidemiology of bacterial infections in patients with cirrhosis hospitalised for a bacterial infection or developing a bacterial infection during their hospital stay.
      • Piano S.
      • Singh V.
      • Caraceni P.
      • Maiwall R.
      • Alessandria C.
      • Fernandez J.
      • et al.
      Epidemiology and effects of bacterial infections in patients with cirrhosis worldwide.
      In these patients, the incidence of infections caused by MDR bacteria was not higher among those who received norfloxacin than among those who did not.
      • Piano S.
      • Singh V.
      • Caraceni P.
      • Maiwall R.
      • Alessandria C.
      • Fernandez J.
      • et al.
      Epidemiology and effects of bacterial infections in patients with cirrhosis worldwide.
      So, on clinical grounds, while waiting for new options for SBP prophylaxis, the most important message that can also be drawn from the most recent findings
      • Moreau R.
      • Elkrief L.
      • Bureau C.
      • Perarnau J.M.
      • Thévenot T.
      • Saliba F.
      • et al.
      Effects of long-term norfloxacin therapy in patients with advanced cirrhosis.
      • Piano S.
      • Singh V.
      • Caraceni P.
      • Maiwall R.
      • Alessandria C.
      • Fernandez J.
      • et al.
      Epidemiology and effects of bacterial infections in patients with cirrhosis worldwide.
      is that patients with an indication for primary or secondary prophylaxis of SBP should continue to receive quinolones with few exceptions, raising the level of clinical monitoring for the potential development of adverse effects.
      In conclusion, the most recent finding,
      • Moreau R.
      • Elkrief L.
      • Bureau C.
      • Perarnau J.M.
      • Thévenot T.
      • Saliba F.
      • et al.
      Effects of long-term norfloxacin therapy in patients with advanced cirrhosis.
      • Piano S.
      • Singh V.
      • Caraceni P.
      • Maiwall R.
      • Alessandria C.
      • Fernandez J.
      • et al.
      Epidemiology and effects of bacterial infections in patients with cirrhosis worldwide.
      added to those already existing,
      • Ginés P.
      • Rimola A.
      • Planas R.
      • Vargas V.
      • Marco F.
      • Almela M.
      • et al.
      Norfloxacin prevents spontaneous bacterial peritonitis recurrence in cirrhosis: results of a double-blind, placebo-controlled trial.
      • Fernández J.
      • Navasa M.
      • Planas R.
      • Montoliu S.
      • Monfort D.
      • Soriano G.
      • et al.
      Primary prophylaxis of spontaneous bacterial peritonitis delays hepatorenal syndrome and improves survival in cirrhosis.
      justify, on the methodological level, the recommendations on the prophylaxis of SBP reported in the EASL CPGs for the management of patients with decompensated cirrhosis. Indeed, recommendations should be based on evidence and not on considerations or speculations, which may certainly be valid and shareable, at least in part as in this case, but have the limit of remaining what they are.

      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:

      References

        • EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis
        J Hepatol. 2018; 69: 406-460
      1. Europen Medicines Agency. Disabling and potentially permanent side effects lead to suspension or restrictions of quinolone and fluoroquinolone antibiotics. 2018;44.

        • 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.
        JAMA Intern Med. 2015; 175: 1839-1847
        • Lee C.C.
        • Lee M.G.
        • Hsieh R.
        • Porta L.
        • Lee W.C.
        • Lee S.H.
        • et al.
        Fluoroquinolone and the risk of aortic dissection.
        J Am Coll Cardiol. 2018; 72: 1369-1378
        • Pasternak B.
        • Inghammar M.
        • Svanström H.
        Fluoroquinolone use and risk of aortic aneurysm and dissection: Nationwide cohort study.
        BMJ. 2018; 360: 1-8
      2. European Centre for Disease Prevention and Control (ECDC). Antimicrobial resistance surveillance in Europe 2015.

        • Goel A.
        • Rahim U.
        • Nguyen L.H.
        • Stave C.
        • Nguyen M.H.
        Rifaximin for the prophylaxis of spontaneous bacterial peritonitis: a systematic review.
        Aliment Pharmacol Ther. 2017; 46: 1029-1036
        • Fernández J.
        • Navasa M.
        • Gómez J.
        • Colmenero J.
        • Vila J.
        • Arroyo V.
        • et al.
        Bacterial infections in cirrhosis: epidemiological changes with invasive procedures and norfloxacin prophylaxis.
        Hepatology. 2002; 35: 140-148
        • Marciano S.
        • Dirchwolf M.
        • Diaz J.M.
        • Bermudez C.
        • Gutierrez-Acevedo M.N.
        • Barcán L.A.
        • et al.
        Spontaneous bacterial peritonitis recurrence in patients with cirrhosis receiving secondary prophylaxis with norfloxacin.
        Eur J Gastroenterol Hepatol. 2018; ([Epub ahead of print])https://doi.org/10.1097/MEG.0000000000001331
        • Gascón I.
        • Pascual S.
        • Plazas J.
        • Sánchez J.
        • Francés R.
        • Más P.
        • et al.
        Norfloxacin decreases bacterial adherence of quinolone-resistant strains of Escherichia coli isolated from patients with cirrhosis.
        Aliment Pharmacol Ther. 2005; 21: 701-707
        • Moreau R.
        • Elkrief L.
        • Bureau C.
        • Perarnau J.M.
        • Thévenot T.
        • Saliba F.
        • et al.
        Effects of long-term norfloxacin therapy in patients with advanced cirrhosis.
        Gastroenterology. 2018; 155: 1816-1827
        • Piano S.
        • Singh V.
        • Caraceni P.
        • Maiwall R.
        • Alessandria C.
        • Fernandez J.
        • et al.
        Epidemiology and effects of bacterial infections in patients with cirrhosis worldwide.
        Gastroenterology. 2018; (pii: S0016-5085(18)35402-7 [Epub ahead of print])https://doi.org/10.1053/j.gastro.2018.12.005
        • Ginés P.
        • Rimola A.
        • Planas R.
        • Vargas V.
        • Marco F.
        • Almela M.
        • et al.
        Norfloxacin prevents spontaneous bacterial peritonitis recurrence in cirrhosis: results of a double-blind, placebo-controlled trial.
        Hepatology. 1990; 12: 716-724
        • Fernández J.
        • Navasa M.
        • Planas R.
        • Montoliu S.
        • Monfort D.
        • Soriano G.
        • et al.
        Primary prophylaxis of spontaneous bacterial peritonitis delays hepatorenal syndrome and improves survival in cirrhosis.
        Gastroenterology. 2007; 133: 818-824