Discussion on prophylactic antibiotic treatment in patients with predicted severe pancreatitis: A placebo-controlled, double-blind trial

September 2004

CORRESPONDENCE

GIN-HO LO, M.D. KWOK-HUNG LAI, M.D. Division of Gastroenterology Department of Medicine Kaohsiung Veterans General Hospital National Yang-Ming University Kaohsiung, Taiwan 1. Ryan BM, Stockbrugger RW, Ryan JM. A pathophysiologic, gastroenterologic, and radiologic approach to the management of gastric varices. Gastroenterology 2004;126:1175–1189. 2. Laine L. Ligation: endoscopic treatment of choice for patients with bleeding esophageal varices (editorial)? Hepatology 1995; 22:663– 665. 3. Lo GH, Lai KH, Cheng JS, Hwu JH, Chang CF, Chen SM, Chiang HT. A prospective, randomized trial of sclerotherapy versus ligation in the management of bleeding esophageal varices. Hepatology 1995;22:466 – 471. 4. Lo GH, Lai KH, Cheng JS, Chen MH, Chiang HT. A prospective, randomized trial of butyl cyanoacrylate injection versus band ligation in the management of bleeding gastric varices. Hepatology 2001;33:1060 –1064. 5. Lo GH, Lai KH. Is endoscopic ligation therapy with large detachable snares and elastic bands really safe and effective? Gastrointest Endosc 2003;57:438 – 439. 6. Oho K, Iwano T, Sumino M, Toyonaga A, Tanikawa K. Ethanolamine oleate versus butyl cyanoacrylate for bleeding gastric varices: a non-randomized study. Endoscopy 1995;27:349 –354. 7. Sarin SK, Primignani M, Agarwal SR. Gastric varices. In: de Franchis R, ed. Portal hypertension III, Proceedings of the third Baveno International consensus workshop on definitions, methodology and therapeutic strategies. Oxford, England: Blackwell Science, 2001;76 –94. 8. Sarin SK. Long-term follow-up of gastric variceal sclerotherapy: an eleven-year experience. Gastrointest Endosc 1997;46:8 –14. 9. Chiu KW, Changchien CS, Chuah SK, Tai DI, Chiou SS, Lee CM, Chen JJ. Endoscopic injection sclerotherapy with 1.5% sotradecol for bleeding cardiac varices. J Clin Gastroenterol 1997;24:161– 164. 10. Chang KY, Wu CS, Chen PC. Prospective, randomized trial of hypertonic glucose water and sodium tetradecyl sulfate for gastric variceal bleeding in patients with advanced liver cirrhosis. Endoscopy 1996;28:481– 486. doi:10.1053/j.gastro.2004.07.043

Reply. We appreciate the generous comments of Drs. Lo and Lai regarding our recent review of the treatment options for gastric varices (GV). Their comments highlight some of our own contentions regarding GV namely that there are few randomized controlled studies for therapies of GV, and still fewer where GV have been subclassified. The correspondents take issue with our comments regarding the treatment of GOV1. The results of endoscopic variceal sclerotherapy (EVS) for treatment of GOV1 are without doubt better than the results of this treatment for GOV2 or IGV. We acknowledged this data and suggested that EVS is an appropriate option in the treatment of GOV1 but certainly not appropriate in treatment of the other subtypes of GV. In Table 1, the primary hemostasis rate for EVS in GOV1 should have included the lower limit of 67%. We certainly did not intend to imply, nor do we believe that we did imply “between the lines” that EVS is the treatment of choice for treatment of GOV1, but merely that it is an appropriate option. GOV1 are a direct extension of esophageal varices (EV), extending along the lesser curve of the stomach: the distal end of the EV and the proximal

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margin of the GV is difficult and/or impossible to determine. As a result of this, there has been consensus in the past few years that GOV1 could be treated as for EV,1,2 be that with EVS or endoscopic variceal band ligation (EVL). Indeed our own preference is for EVL when the varix size permits, although to date there are no published data for EVL in GOV1. We do not agree with the correspondents contention that “it is now well recognized that EVS is unsuitable in the management of GV,” as several academic bodies cite it as an appropriate option for GOV1, supported by, albeit, incomplete data.2 We agree that endoscopic variceal obturation (EVO) is highly effective in the treatment of GV of all types, and is the treatment of choice in fundal varices and IGV, and may well be proven to be the treatment of choice for GOV1 also. In the proposed treatment algorithm (Figure 6), we should have included the option of EVO as an alternative to “EV treatment pathways” as a first line treatment of GOV1, as was implicit in the text. We thank Drs. Lo and Lai for their interest in our article and believe that their thoughtful comments again indicate that the optimal treatment of GV still remains to be determined. Randomized controlled studies with accurate subclassification of the GV, adequate patient numbers, and prospective design are needed to answer the many questions that remain. BARBARA M. RYAN REINHOLD W. STOCKBRUGGER J. MARK RYAN Department of Clinical Medicine St. James Hospital Dublin, Ireland 1. Sarin SK, Primignani M, Agarwal SR. Gastric varices. In: de Franchis R, ed. Portal hypertension. Proceedings of the third Baveno international consensus workshop on definitions, methodology and therapeutic strategies. London: Blackwell Science, 2001: 76 –96. 2. Jalan R, Hayes PC. UK guidelines on the management of variceal haemorrhage in cirrhotic patients. British Society of Gastroenterology. Gut 2000;46(Suppl. 3-4):III1–III15. doi:10.1053/j.gastro.2004.07.044

Discussion on Prophylactic Antibiotic Treatment in Patients With Predicted Severe Pancreatitis: A Placebo-Controlled, Double-Blind Trial Dear Sir: The manuscript by Isenmann et al. further contributes to our understanding of the problems involving prophylactic use of antibiotics in severe necrotizing pancreatitis patients.1 The multicenter, randomized, double-blind design of the study, together with the size of the patient population seem to confer greater weight to its conclusion, namely to not make use of prophylactic antibiotics. However, several limits exist that render the conclusions indefinite in our opinion. The authors claim that the aim of the study is to clarify if prophylactic antibiotic treatment, associated with 400 mg ciprofloxacin IV/500 mg metronidazole IV twice daily is significantly superior to placebo in reducing the incidence of infection of pancreatic necrosis. With this aim in mind, it is evident that the study population must be enrolled only on the basis of the presence of necrosis and not upon criteria that are predictive of severity. The criteria chosen by the authors are unfortunately, inadequate for the scope of the study. This

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includes 78 necrotizing pancreatitis patients out of the 114 enrolled, and this number is destined toward further diminution (to 58) if only patients in which the extension of necrosis was measured, based on the only valid criteria available, namely CT (see Table 5 in the manuscript). In this aspect, the study is not more numerous than previous studies,2–9 which even if different experimental criteria are used, suffer from the same problem. The analysis of the results should accordingly concern this latter subgroup of patients and not the entire cohort of 114. If only this subpopulation is considered, 33 patients were treated while 25 patients were given placebo, with a frequency of infected necrosis of 18% and 16%, respectively. It would interesting to know the times of occurrence of complications in the 2 groups and in how many cases the diagnosis of infected necrosis was made either intraoperatively or by FNA. In this regard, among the bacteria isolated from the infected necrosis it is surprising to find 5 Staphylococcus epidermidis coagulase negative strains at the top of the list. To our best knowledge, the detection of this species might be considered more a contamination than a true infection. Moreover, once the presence of infected necrosis was determined, it was not clear if surgical intervention was immediate or if this was preceded by the open administration of antibiotics. Apart from these considerations, the fact remains that in our opinion, the conclusions of the study should be limited to the fact that, in contrast to other antibiotic regimes or associations, the association between ciproxin and metronidazole at the doses given, with respect to placebo, does not reduce the incidence of infected necrosis. Nonetheless, the considerations made by the authors concerning “on-demand” antibiotics merit comment. Is this really more economically favorable, not considering the clinical course with respect to prophylactic use in patients with necrotizing pancreatitis? The definitive answer to this question is still forthcoming. It will undoubtedly be provided by the experimental design furnished by the authors, although it should be applied to a larger patient population that is better selected for the presence of necrosis. Until now, however, even considering the confusion that exists on the subject, we believe that the decision to treat patients with necrotizing pancreatitis with prophylactic antibiotics should be made on the basis of meta-analysis studies carried out to date, which favor their use.10 Lastly, in our opinion the only significant result from the present study is the frequency of patients who on the basis of the study protocol were switched to open treatment: 28% in the antibiotic group and 46% in the placebo group (P ⬍ 0.05). These data could suggest not only the need, but the inevitability, in the everyday clinical setting practice, of prescribing early antibiotic treatment in the management of severe necrotizing pancreatitis, either prophylactically or “on demand.” CLAUDIO BASSI, M.D. MASSIMO FALCONI, M.D. Surgical and Gastroenterological Department University of Verona Verona, Italy 1. Isenmann R, Runzi M, Kron M, Kahl S, Kraus D, Jung N, Maier L, Malfertheiner P, Goebell H, Beger HG, German Antibiotics in Severe Acute Pancreatitis Study Group. Prophylactic antibiotic treatment in patients with predicted severe acute pancreatitis: a placebo-controlled, double-blind trial. Gastroenterology 2004;126: 997–1004. 2. Howes R, Zuidema GD, Cameron JL. Evaluation of prophylactic antibiotics in acute pancreatitis. J Surg Res 1975;18:197–200. 3. Craig RM, Dordal E, Myles L. The use of ampicillin in acute pancreatitis. Ann Intern Med 1975;83:831– 832.

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4. Finch WT, Sawyers JL, Schenker S. A prospective study to determine the efficacy of antibiotics in acute pancreatitis. Ann Surg 1976;183:667– 671. 5. Pederzoli P, Bassi C, Vesentini S, Campedelli A. A randomized multicenter clinical trial of antibiotic prophylaxis of septic complications in acute necrotizing pancreatitis with imipenem. Surg Gynecol Obstet 1993;176:480 – 483. 6. Luiten EJT, Hop WCJ, Lange JF, Bruining HA. Controlled clinical trial of selective decontamination for the treatment of severe acute pancreatitis. Ann Surg 1995;222:57– 65. 7. Sainio V, Kemppainen E, Puolakkainen P, et al. Early antibiotic treatment in acute necrotising pancreatitis. Lancet 1995;346: 663– 667. 8. Delcenserie R, Yzet T, Ducroix JP. Prophylactic antibiotics in treatment of severe acute alcoholic pancreatitis. Pancreas 1996; 13:198 –201. 9. Bassi C, Falconi M, Talamini G, et al. Controlled clinical trial of Pefloxacin versus Imipenem in severe acute pancreatitis. Gastroenterology 1998;115:1513–1517. 10. Bassi C, Larvin M, Villatoro E. Antibiotic therapy for prophylaxis against infection of pancreatic necrosis in acute pancreatitis. Cochrane Database Syst Rev 2003;4: CD002941. doi:10.1053/j.gastro.2004.07.045

Reply. We would like to reply to the critical comments of Drs. Bassi and Falconi on our recent paper.1 We have conducted the first double-blind, placebo-controlled study on antibiotics in severe acute pancreatitis. Drs. Bassi and Falconi have problems with the inclusion criteria of our study, which we cannot share. It is evident that the majority of gastroenterologists and gastrointestinal surgeons base the indication for prophylactic antibiotics in acute pancreatitis rather on clinical than on CECT findings.2,3 Therefore, we decided to base enrollment on the factors that are generally accepted to define severity of pancreatitis, namely serum C-reactive protein or CECT. Using CECT as an exclusive criteria for study inclusion (as suggested by Drs. Bassi and Falconi) it is obvious, that we would have missed a considerable number of patients with severe acute pancreatitis in whom pancreatic necrosis became evident after the first 72 hours after onset of clinical symptoms. As the study population represents the typical cohort of patients with predicted severe acute pancreatitis, we think that the statement of Drs. Bassi and Falconi that the analysis of results should be limited to the subgroup of 58 patients with a defined extend of pancreatic necrosis and not to the intention to treat group of 114 patients is inadequate. The second point addresses the bacterial spectrum of our patients with infected necrosis. All but 2 cases with infected necrosis underwent surgical necrosectomy where intraoperative smears confirmed the bacteriologic findings. The bacterial spectrum of 2 patients with infected necrosis not undergoing surgical necrosectomy comprised Escherichia coli and Enterobacter spp. Therefore, we think that our bacteriological data from infected necrosis truly represent infection and not contamination, as supposed by Drs. Bassi and Falconi. The antibiotic combination in our study, Ciprofloxacin and metronidazole, has been chosen after careful consideration of pharmacokinetic, experimental, and clinical properties of these drugs in severe intra-abdominal and/or pancreatic infection.4 – 6 The point of Drs. Bassi and Falconi, that this combination (in contrast to other antibiotic regimes) does not reduce the incidence of infected necrosis is not correct. It must be noted, that until now, only 2 studies with parenteral Imipenem have shown a significant reduction of the incidence of infected necrosis.7,8 Recent data with Meropenem, another broad-spectrum Carbapenem similar to Imipenem, could not confirm