GASTROENTEROLOGY

SELECTED

1991;101:559-557

SUMMARIES

Mark Feldman, M.D.

Selected Summaries Editor Dallas Veterans Administration Medical Service (111) Dallas, Texas 75216

Medical Center

STAFF James L. Achord, Jackson, MS Kim E. Barrett, San Diego, CA

Charles 0. Elson, Birmingham, AL Grace H. Elta, Ann Arbor, MI Lawrence S. Friedman, Philadelphia, PA Hans Fromm, Washington, DC Hans Gerdes, New York, NY

OF CONTRIBUTORS

Samuel Klein, Galveston,

TX

Raymond S. Koff, Framingham, MA Benjamin Krevsky, Philadelphia, PA Loren Laine, Los Angeles, CA Peter F. Malet, Philadelphia, PA Thomas A. Miller, Houston, TX Joel E. Richter, Birmingham, AL

ANTIBIOTIC PROPHYLAXIS FOR PREVENTION OF SPONTANEOUS BACTERIAL PERITONITIS? Gines P, Rimola A, Planas R, et al. (Hospital Clinic i Provincial of Barcelona, Spain; Hospital Germans Trias i Pujol of Badalona, Spain; Hospital de la Vall d’Hebro of Barcelona, Spain; Hospital Mutua of Terrassa, Sevilla, Spain; and Residencia Virgen de1 Rocio of Sevilla, Spain). Norfloxacin prevents spontaneous bacterial peritonitis recurrence in cirrhosis: results of a double-blind, placebocontrolled trial, Hepatology 1990;12:716-724. Spontaneous bacterial peritonitis (SBP) is a frequent complication of cirrhosis. Most episodes of SBP are caused by gram-negative aerobic bacilli that normally reside in the intestine. The present prospective, double-blind, placebocontrolled trial was designed to assess whether the longterm administration of norfloxacin, an antibiotic highly active against aerobic gram-negative bacilli, could prevent SBP recurrence in patients with cirrhosis. Eighty cirrhotic patients who had recovered from an episode of SBP were enrolled. SBP was diagnosed by the following criteria: (a) abdominal pain and/or fever, (b) ascitic polymorphonuclear cell count > 350/mm3, and (c) absence of features of secondary peritonitis. Following antibiotic treatment, resolution of SBP was confirmed in all cases by resolution of clinical and laboratory abnormalities and negative ascitic fluid culture. Patients were excluded from participating if (a) prothrombin time was < 25%, (b) serum bilirubin level was > 10 mg/dL, (c) serum creatinine level was > 2 mg/dL, or (d) the patient had chronic hepatic encephalopathy or features suggestive of hepatocellular carcinoma. Forty patients were randomized to norfloxacin (400 mg) and 40 patients to placebo, once daily by mouth, starting 1 week after resolution of the index episode of SBP. At inclusion, both groups were comparable with respect to etiology of cirrhosis, laboratory data, ascitic fluid protein and polymorphonuclear cell concentrations, number of prior episodes of SBP, and causative organism. Patients were followed up in the outpatient clinic monthly for 3

Caroline A. Riely, Memphis,

TN

Mitchell L. Schubert, Richmond, VA Konrad Schulze-Delrieu, Iowa City, IA Joseph Sweeting, New York, NY Dwain L. Thiele, Dallas, TX Richard C. Thirlby, Seattle, WA M. Michael Wolfe, Boston, MA

months, then bimonthly thereafter. Compliance was determined at each visit by pill count and urine examination for the presence of norfloxacin by high-performance liquid chromatography. Fourteen (35%) patients from the placebo group and 5 (13%) from the norfloxacin group developed recurrent SBP (P = 0.01; mean follow-up, 6.4 f 0.6 months). In the placebo group, 10 of the 14 SBP recurrences were caused by gram-negative bacteria (Escherichia coli, 8; Citrobacferfreundii, 1; and Salmonella species, l), whereas in the norfloxacin group, only 1 of the 5 cases (in a noncompliant patient) was caused by gram-negative bacteria (E. coli) (P < 0.01). The other 4 cases of SBP’ in the norfloxacin group were caused by Streptococcus species. The overall probability of SBP recurrence at 1 year of follow-up was decreased from 68% to 20% (P < O.Ol), while the probability of SBP from gram-negative bacilli was decreased from 60% to 3% (P < 0.01) in the norfloxacin group. Over the study period, 7 patients in the norfloxacin group died compared with 10 in the placebo group (NS). Only 1 patient in the norfloxacin group experienced a side-effect related to treatment-esophageal candidiasis which responded to nystatin. Infections other than SBP occurred in 3 norfloxacin-treated patients and 5 placebotreated patients; none were due to resistant or exotic organisms. The authors conclude that long-term selective intestinal decontamination with norfloxacin is an effective and safe method to prevent recurrence of SBP in cirrhotic patients. Spontaneous bacterial peritonitis is a frequent compliComment. cation of cirrhosis, present at admission or during hospitalization in lo%-25% of cirrhotic patients (Dis Mon 1985;31:1-48; Hepatology 1990;12:776-781). Particularly prone are patients with low ascitic protein or C3 concentrations (Gastroenterology 1986;91: 1343-1346; Dig Dis Sci 1989;34:1547-1552). The overall mortality from a given episode of SBP is about 3O%, and more than 50% of patients who survive the initial episode will have a recurrence within a year (Hepatology 1988;8:27-31; Hepatology 1988;8:171175; Hepatology 1989;9:423-426). The mortality is considerably higher in patients with acute liver disease than in patients with otherwise stable cirrhosis (Hepatology 1982;2:399-407). Development of a safe, effective, and inexpensive therapy to prevent SBP would be an important advance.

August 1991

Gines et al. are to be commended for their excellent study. This is the first prospective, double-blind, placebo-controlled trial to examine the efficacy of antibiotic prophylaxis in preventing SBP in cirrhotic patients. Daily norfloxacin dramatically reduced the incidence of recurrent SBP. The authors confirmed the efficacy and selectivity of norfloxacin in eradicating gram-negative bacteria from the intestine by quantitative stool cultures. In 6 patients from the norfloxacin group, aerobic gram-negative bacilli were eradicated from the fecal flora in all patients, whereas in 6 patients from the placebo group no significant change in fecal flora was detected. Besides eradicating gram-negative bacteria from the gut, norfloxacin may reduce SBP by increasing complement components in serum and ascites (Hepatology 1990;12:1175-1178) and achieving blood levels capable of suppressing transient bacteremia (Antimicrab Agents Chemother 1982;21:604-607). Approximately 70% of an oral dose of norfloxacin is absorbed from the intestine, resulting in blood levels exceeding the minimum inhibitory concentration of most gram-negative bacteria. Before a general recommendation concerning the use of norfloxacin in cirrhotic patients with ascites can be made, we need to consider whether the benefits indeed outweigh the long-term risks. Most cases of SBP are caused by aerobic gram-negative bacteria that normally reside in the gut (N Engl J Med 1982;307:83-93). The gut flora of cirrhotic patients is qualitatively and quantitatively similar to that of the normal population (Gastroenterology 1970;59: 70-74). Intermittent transient bacteremia, however, is more common in cirrhotic patients for a variety of reasons (decreased resistance to gram-negative bacterial overgrowth, decreased integrity of the intestinal mucosa due to venous congestion and thrombocytopenia, increased intrahepatic shunting, and decreased bacterial clearance by the reticuloendothelial system) (Hepatology 1984; 4:53-58; Dis Mon 1985;31:1-48). In this setting, peritoneal seeding may occur, particularly when ascitic protein and complement concentrations and opsonic activity are decreased. Broad-spectrum antibiotic prophylaxis aimed at eradicating gut pathogens has not been useful because of the development of resistant bacteria and the overgrowth of unusual organisms and fungi. Recent experience with granulocytopenic patients has shown that selective intestinal decontamination, i.e., eradication of aerobic gram-negative bacilli from the intestinal flora with preservation of the remaining aerobic and anaerobic bacteria, can reduce the frequency of gram-negative bacteremia in this high-risk population [J Infect Dis 1981;143:644-654; Am J Med 1987;82(Suppl 6B):40461. Norfloxacin, an analogue of nalidixic acid, is an ideal agent for selective bacterial decontamination because (a) it is incompletely absorbed by the intestine, (b) it is active against most aerobic gram-negative bacteria with little or no activity against grampositive and anaerobic organisms, and (c) emergence of resistance is low (Ann Intern Med 1988;108:238-251). Norfloxacin inactivates bacterial DNA gyrase and thus kills bacteria by interfering with DNA synthesis and repair. Long-term antibiotic therapy carries potential risks. The duration of the present study was only 6 months, whereas the risk of SBP in a cirrhotic patient with ascites is lifelong. Although the emergence of resistance to quinolones is expected to be a slow process and was not seen in the present study, acquisition of resistance to quinolanes has been clearly shown in other clinical situations. Specifically, the use of ciprofloxacin, another quinolone, to treat methicillin-resistant Stoph_v~ococcus aureus (MRSA) has resulted in resistant strains (J Clin Microbial 1989;27:335-336; Antimicrob Agents Chemother 1989;33:593-594). Also, in patients with cystic fibrosis, chronic prophylaxis with ciprofloxacin has led to the emergence of resistant strains of pseudomonas (Lancet 1987;1:235-237). It is likely that long-term prophylaxis with norfloxacin would shift the spectrum of microbial agents causing SBP from gramnegative aerobes to gram-positive organisms such as Streptococcus

SELECTED SUMMARIES

551

pneumoniae

and Enterococcus faecalis. This has already occurred with selective intestinal decontamination in the granulocytopenic population [Rev Infect Dis 1989;ll(Suppl 5):S1231-S1236]. Indeed, Gines et al. report that 4 of the 5 cases of recurrent SBP in the norfloxacin group were caused by Streptococcus species (S. sanguis, S. milleri, S. viridans, and S. pneumoniae). Finally, the issue of cost and cost-effectiveness must be considered. In Virginia, a 400-mg norfloxacin tablet averages $3.00, or about $1000 for a 12-month supply. It should be emphasized that absolute benefit for norfloxacin was not shown in this study. Although norfloxacin prophylaxis decreased the incidence of recurrent SBP, it did not improve survival, decrease morbidity, or reduce hospital admissions compared with a “diagnose and treat” strategy. It should be noted, however, that patients enrolled in this study represented a homogeneous, otherwise stable group of cirrhotic patients with a relatively good prognosis; patients with poor liver function, azotemia, or encephalopathy were specifically excluded. In such a group, it would take a sample size of more than 800 patients to show a 50% decrease in mortality. Therefore, it is premature to recommend long-term norfloxacin prophylaxis for all patients following an episode of SBP. These provocative findings need to be confirmed by other investigators in a larger number of patients followed up for longer periods. In the meantime, short-term norfloxacin prophylaxis might be considered for certain high-risk cirrhotic patients in whom an episode of SBP would carry a very high risk of mortality, such as those hospitalized with variceal bleeding or acute liver decompensation (e.g., alcoholic hepatitis) or those awaiting liver transplantation. M. L. SCHUBERT,M.D. A. J. SANYAL,M.D. E. S. WONG. M.D. Reply. We greatly appreciate the discussion of Schubert et al. concerning our study on norfloxacin for prevention of SBP recurrence in patients with cirrhosis (Hepatology 1990;12:716-724). However, we would like to make some comments. First, it is important to emphasize that the only end point of our study was SBP recurrence and not survival. Accordingly, treatment with norfloxacin or placebo was definitively interrupted in patients developing a new episode of SBP. The evaluation of the effect of treatment on survival would have required that patients continue on norfloxacin or placebo treatment following recovery of SBP recurrence. Therefore, no conclusions can be drawn with respect to survival. Norfloxacin proved to be extremely effective in reducing the rate of SBP recurrence (the end point of the trial). Second, although there may be some concern with respect to the long-term use of an antibiotic therapy, no overgrowth by resistant bacteria in fecal cultures were observed. Furthermore, colonization by resistant bacteria was not documented in any patient of this study after a follow-up period of up to 24 months (unpublished observations). Third, cost-effectiveness seems to be a conflicting issue of norfloxacin prophylaxis in the United States (Hepatology 1990;12:776781). In Spain, a l-year treatment with norfloxacin, 400 mg/day, costs $551, whereas the cost for a 7-day hospitalization to treat an episode of SBP averages $2,154. Considering that patients not receiving norfloxacin have a three times higher risk of developing SBP than those treated with norfloxacin (relative risk, 2.8; 95% confidence interval, 1.19-6.61), a reduction in the cost of treatment is obtained by using norfloxacin prophylaxis. Thus, cost-effectiveness analysis also supports the “prophylactic” strategy and not the “diagnose and treat” strategy. Finally, in our opinion selective intestinal decontamination with antibiotics is indicated for prevention of bacterial infections in cirrhosis not only in patients who have recovered from an episode of SBP but also in those with gastrointestinal hemorrhage (Hepatology 1985;5:463-467). The use of prophylactic antibiotic therapy in these two situations has

Antibiotic prophylaxis for prevention of spontaneous bacterial peritonitis?

GASTROENTEROLOGY SELECTED 1991;101:559-557 SUMMARIES Mark Feldman, M.D. Selected Summaries Editor Dallas Veterans Administration Medical Service...
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