- Email: [email protected]
THE ROLE OF ANTIBIOTIC PROPHYLAXIS IN THE TREATMENT OF ACUTE PANCREATITIS
PANCREAS UPDATE
0889-8553/99 $8.00
+ .OO
THE .ROLE OF ANTIBIOTIC PROPHYLAXIS IN THE TREATMENT OF ACUTE PANCREATITIS Manfred Ratschko, Thomas Fenner, MD, and Paul Georg Lankisch, MD
Infection of the pancreas has been a dreaded complication of acute pancreatitis for many years.33Before the availability of computed tomography (CT), patients with severe pancreatitis were treated for at least 4 to 6 weeks before surgery was resorted to as a last life-saving effort in seriously ill, nearly moribund patients. In most of these patients, pancreatic necrosis involved infections, and the patient invariably required several relaparotomies for d6bridement of residual infected tissue. Mortality generally exceeded 50%. The situation has now changed with the availability of contrast-enhanced CT in most centers and ultrasoundguided or CT-guided aspiration of pancreatic necrosis for diagnosing pancreatic infection. Both procedures constitute the gold standards for detecting pancreatic necrosis and infection, thus enabling surgeons to perform pancreatic d6bridement at an earlier stage in patients with infected pancreatic necrosis or sterile necrosis with persistence of systemic These detection methods raised the question of whether an antibiotic could or should be administered prophylactically to improve the clinical course and patient survival rate. The question has led to considerable controversy5,28, 45 Johnsonz9reviewed experimental and clinical
From the Central Pharmacy (MR), and the Department of Medicine (PGL), Municipal Clinic of Liineburg, Liineburg; and the Institute for Clinical Pathology and Microbiology (TF), Hamburg, Germany GASTROENTEROLOGY CLINICS OF NORTH AMERICA
-
VOLUME 28 NUMBER 3 SEPTEMBER 1999
641
642
RATSCHKO et a1
studies relating to antibiotic prophylaxis in acute pancreatitis. The authors critically review available data and review the approach to this frequent clinical debate. INFECTION IN ACUTE PANCREATITIS
It is difficult to estimate the prevalence of pancreatic infection because most reports are from tertiary referral centers with a vested interest in the disease. Acute interstitial pancreatitis is estimated to occur in approximately 80% of acute pancreatitis cases and necrotizing pancreatitis in the remaining 20%. Infection in necrotizing pancreatitis occurs in 40% and is either a spreading infection of devitalized tissue in the retroperitoneum (infected necrosis) or a localized abscess.", 12, l9 Infections develop within the first 2 weeks of illness after admission to the hospital, which is usually shortly after onset of symptoms, in approximately 50% of necrotizing pancreatitis cases, and in 71%, infections develop within the first 3 weeks of illne~s.~, 22 A pancreatic abscess has not been detected before the first month of illness11,19 and thus is a later onset than infected necrosis. Although the gold standard for diagnosing pancreatic necrosis is the dynamic contrast-enhanced CT scan, this procedure is not helpful for diagnosing infection. The only signs of infection that can be detected are air bubbles in and around pancreatic necrosis. Otherwise, there is no particular feature on contrast-enhanced CT that permits distinguishing infected from sterile necrosis. Clinically, pancreatic infection may be suspected on the basis of unresolved organ failure, persisting systemic toxicity, or both. In this case, ultrasound-guided or CT-guided percutaneous aspiration of suspected pancreatic tissue with bacteriologic sampling should be performed. Needle aspirates should be obtained from areas of necrosis using a 20- to 22-gauge needle via a route that avoids the colon. Because of the importance of not transgressing the colon and thereby risking inoculation of colonic flora into the retroperitoneum, it is recommended that patients receive oral contrast agents routinely to opacify the colon when the aspiration is CT guided. Fluid obtained should be carried by hand immediately to the bacteriology laboratory for Gram staining and culture (for aerobic and anaerobic bacteria and fungi).33Gram stain has proven to be reliable as an early indicator of pancreatic infection. In one retrospective study, there was no instance of a positive Gram staining followed by a negative culture, and in almost all cases of a positive culture, the Gram stain also revealed organism^.^ The fact that colonic-type bacteria frequently cause pancreatic infection has led to the theory that the gut acts as a reservoir from which bacteria can translocate to colonize pancreatic necrosis and acute fluid collections resulting in infected pancreatic necrosis and pancreatic abs c e ~ s e sThere . ~ ~ is supporting evidence for this in experimental studies39, 47,52 showing that bacteria are able to reach the gland from the colon by direct transmural spread. Once infections are identified, appropriate
ANTIBIOTIC PROPHYLAXIS IN THE TREATMENT OF ACUTE PANCREATITIS
643
antibiotics should be prescribed. Infected necrosis is usually treated by prompt surgical dkbridement? 37 whereas an abscess may be treated either by a pigtail catheter drainage or by surgical drainage.2,11, l9 Although using antibiotic treatment in the case of proven infection raises no questions, there is considerable discussion concerning antibiotic prophylaxis in acute pancreatitis. Some studies have reported the incidence of microorganism-associated secondary infection in patients with pancreatic infection, infected necrosis, abscess, or pseudocyst (Table 1). It appears that the data concerning monomicrobial and polymicrobial infections are not uniform. Further studies are required. Currently, it seems that in cases of pancreatic abscess, polymicrobial infections are more frequent.l’,l9 Among gram-negative aerobic microorganisms, Escherichia coli and other enterobacteriaceae are most frequent, whereas among the gram-positive aerobic microorganisms, staphylococci and enterococci are the most frequent. Anaerobic and fungal infections are uncommon, but it is believed that an increased usage of antibiotics may spark the prevalence of the PENETRABILITY OF ANTIBIOTICS INTO HUMAN PANCREATIC FLUID AND TISSUE
To select antibiotics for the treatment of acute pancreatitis or for the prophylaxis of pancreatic infection, the clinician needs to know whether the antibiotics are able to penetrate into human pancreatic fluid or pancreatic tissue. Because of possibly divergent results obtained in animal experiments and human studies, only human studies were tabulated for reviewing penetrability of antibiotics (Table 2). At present, there are 13 studies showing the effect of antibiotics on the human pancreas, and they differ considerably.* In most studies, the parenteral route of administration for the antibiotics was used, which is appropriate for a patient with acute pancreatitis. Eight studies measured the penetrability of the antibiotic into pancreatic fluid, obtained either on endoscopic retrograde cholangiopancreatography (ERCP) or after stimulation of the 14, ~ 531, , 46 In one studyMthe content of pseudocysts pancreatic fistula.lO, was used to test the penetration of the antibiotic. In the remaining studies, antibiotic contents were looked for in pancreatic tissue. Tissue samples were obtained from patients with different pancreatic diseases and different degrees of inflammation (acute pancreatitis, chronic pancreatitis, pancreatic carcinoma). Human studies15 have shown that the antibiotic level depends on the degree of inflammation, and thus the levels are higher in acute pancreatitis as compared to controls. The authors, listed in the order of date of publication, reported the following results: 41437
Roberts and Williams46failed to detect in pancreatic fluid obtained on *References 7, 10, 14, 15, 18, 25, 30, 31, 34, 4143, 46
BradleyI3 Banks et a14
Fedorak et all9
Berger et a19 Gerzof **
Authors
Pancreatic abscess Infected pseudocyst Infected necrosis Pancreatic infection
Infected necrosis Pancreatic infection Infected necrosis
Nature of Pancreatic Complication
-
53 86
40 78 47 14
60 22
57
-
-
43
Polymicrobial Infections (%)
Monomicrobial Infection (%)
~
47 21
30 35
24
53 24
(%)
E. coli
10 4
20 0
14
5
11
(%)
Pseudomonas
14 35
60 26
34
56 45
(%)
Other Enerobacteriaceae
Gram-Negative Microorganisms ~
2 22
30 17
57
11 12
3 14
40 13
33
13 24
(%)
Enterococci
Gram-Positive Microorganisms Staphylococci(%)
Table 1. MICROORGANISMS ASSOCIATED WITH SECONDARY INFECTION IN ACUTE PANCREATITIS
6 4
-
4
5 9
19
7 -
(%I
Fungi
15 4
9
11 7
Anaerobes (%)
ANTIBIOTIC PROPHYLAXIS IN THE TREATMENT OF ACUTE PANCREATITIS
645
ERCP the antibiotic ampicillin, which was used in the first studies evaluating antibiotics in human acute pancreatitis.l6,20, 26 Benveniste and Morrisloand Lankisch et a134reported sufficient bactericidal concentrations of cefotaxime in both pancreatic juice and pancreatic pseudocysts. Gregg et alZ5tested cephalothin and cefoxitin and failed to find them in pure pancreatic juice obtained from patients with acute relapsing and chronic pancreatitis and controls. Pederzoli et a1 found in pancreatic fluid sufficiently bactericidal concentrations of mez10cillin,4~ciprofloxacin," and ofloxacin.4l Brattstrom et all4 reported only sufficient bactericidal concentrations for clindamycin but not for cefoxitin and piperacillin in patients with pancreas transplants. Koch et a131tested ampicillin, azlocillin, mezlocillin, cefotiam, gentamicin, doxycycline, chloramphenicol, metronidazole, and ciprofloxacin and found sufficient bactericidal concentrations of mezlocillin, ciprofloxacin, metronidazole, doxycycline, and chloramphenicol. Buchler et all5 tested mezlocillin, piperacillin, cefotaxime, ceftizoxime, netilmicin, tobramycin, ofloxacin, ciprofloxacin, imipenem, and metronidazole in patients who underwent pancreatic surgery for acute or chronic pancreatitis or pancreatic carcinoma. Based on the detection of the antibiotics in the pancreatic tissue, three groups of antibiotics were established: group A, substances with low tissue concentrations (netilmicin, tobramycin) that were below the minimal inhibitory concentrations of most bacteria found in pancreatic infection; group B, antibiotics with pancreatic tissue concentrations that were sufficient to inhibit some, but not all, bacteria in pancreatic infection (mezlocillin, piperacillin, ceftizoxime, cefotaxime); and group C, substances with high pancreatic tissue levels as well as high bactericidal activity against most of the germs present in pancreatic infection (ciprofloxacin,ofloxacin, imipenem-cilastatin). The group of Drewelow and Koch18,30 found sufficient bactericidal concentrations of ceftazidime and ofloxacin in pancreatic tissue of patients with a variety of pancreatic diseases. Bassi et a17 tested the penetration of imipenem, mezlocillin, gentamicin, amikacin, pefloxacin, and metronidazole in cases of pancreatic necrosis. Samples were obtained by fine-needle aspiration or during operation or surgical drainage. Gentamicin and amikacin were not detected, whereas the others were found in sufficient bactericidal concentrations. A sufficiently high detection in pancreatic tissue or fluid was found for mezlocillin from the group of penicillins, third-generation cephalosporins, imipenem-cilastatin from the carbapenems group; quinolones, clindamycin, metronidazole, chloramphenicol, and doxycycline. The last two antibiotics, however, should not be used because of the high incidence of serious side effects. The other penicillins as well as firstgeneration and second-generation cephalosporins and aminoglycosides
P-Lactam antibiotics Penicillins Ampicillin Azlocillin Mezlocillin Piperacillin First-generation cephalosporins Cephalothin Second-generationcephalosporins Cefotiam Cefoxitin Third-generation cephalosporins Cefotaxime Ceftazidime Ceftizoxime Carbapenems Imiuenem-cilastatin
Class
+ + + +
+ ?
- 31 - 14, 25
-25
+
+ +
l5
+7
+
15
15
+
+
+ +
+
+
+ 7. 15
+ 31,43 -
-
-
-
15
15
Is
15
15
15
Pancreatic Carcinoma
-
+
+
Chronic Pancreatitis
- 31
Acute Pancreatitis
Detection in Pancreatic Tissue
- 31.34
Detection in Fluid
- 14
-
Oral
+
+ + +
Parenteral
Route of Administration
Table 2. PENETRABILITY OF ANTIBIOTICS INTO HUMAN PANCREATIC JUICE* AND TlSSUEt
Pseudocyst
+ + + + + +
+ + 14
+ 31
+ 31
+
30
+ 7. 15
+7
+
?
-
+ 41
+ 31, 42
+ 15
?
- 15 + 15.30
?
30
- 15
+
*Obtained during endoscopic retrograde cholangiopancreatography or via a pancreatic fistula. tOnly antibiotics tested in the different classes are mentioned. + = Antibiotic detected in sufficiently bactericidal concentration; - = antibiotic not detected or in insufficient bactericidal concentrations.
Other antibiotics Aminoglycosides Amikacin Gentamicin Netilmicin Tobramycin Chloramphenicol Quinolones Ciprofloxacin Ofloxacin Pefloxacin Lincom ycin s Clindamycin Nitroimidazole Metronidazole Tetracyclines Doxycycline ?
?
-
were not found in sufficient amounts in pancreatic fluid or tissue and thus are not helpful in the prophylaxis or treatment of pancreatic infection. ANTIBIOTIC TREATMENT IN SEVERE ACUTE PANCREATITIS: EXPERIMENTAL STUDIES
There are not many experimental studies investigating the effect of prophylactic antibiotics on the prevention of pancreatic infection in acute pancreatitis (Table 3). Widdison et a152studied the effect of cefotaxime applied 12 hours after induction of acute experimental pancreatitis using a perfusion model in cats. They found that cefotaxime reached bactericidal levels in pancreatic tissue and juice and significantly prevented pancreatic infection. Araida et all studied the effect of piperacillin given immediately after induction of acute experimental pancreatitis in the rat (duct model) and found a positive effect both on the infection and or the survival rate. Foitzik et alZ1studied the effect of intravenously applied cefotaxime and imipenem plus the effect of full gut decontamination in a duct hyperstimulation model in the rat. Neither treatment had a positive effect on survival rate, but pancreatic bacterial counts were significantly reduced by imipenem, although not by cefotaxime. Mithofer et a1,38from the same group, used the same model to investigate the effect of imipenem and ciprofloxacin, but in their study the antibiotic treatment was given for 7 days instead of 4 days only. The prolongation of treatment is probably the reason for a positive effect of imipenem on survival rate in this study. Survival rate was also increased by ciprofloxacin. Both antibiotics reduced early and late septic pancreatic complications. ANTIBIOTIC PROPHYLAXIS IN SEVERE ACUTE PANCREATITIS Intravenous Application
Intravenous antibiotic prophylaxis in acute pancreatitis is based on the belief that adequate pancreatic tissue levels of antibiotics can prevent colonization of the inflamed pancreas after translocation of organisms from the gut (Table 4).45Three studies were published in the 1970s in which ampicillin or placebo was randomly given to less than 200 patients with acute pancreatitis, in most cases resulting from alcohol abuse. Only 1 patient of all studies died, and 26 had infectious complications. All studies agreed that ampicillin had no beneficial influence on the clinical *Or 26 For many course of the disease or on serum enyzme elevations.l6< years, this conclusion led to the erroneous impression that antibiotic prophylaxis was of no benefit in pancreatitis. These studies are now recognized to be flawed for several reasons. First, ampicillin has a
rD
Perfusion model Duct model Duct plus hyperstimulation model Duct plus hyperstimulation model
Cat Rat Rat
Rat
Widdison et aP2 Araida et al' Foitzik et alzl
Mithofer et a P
Imipenem Ciprofloxacin
Cefotaxime Piperacillin Imipenem Cefotaxime
Antibiotics
6 h after AEP
12 h after AEP Immediately after AEP 6 h after AEP
Start of Treatment
Positive effect Positive effect
Yes Yes Positive effect No effect
Less Infection
Yest Yes
Not studied Yes No' Yes
Lower Mortality Rate
Biliary Alcohol
Alcohol
Biliary
74 30
23
26
Authors
Pederzoli et a14" Sainio et a14*
Delcenserie et all7
Schwarz et a149
Dominating Cause of Acute Pancreatitis
Patients (n)
Ceftazidime, amikacin, metronidazole Ofloxacin plus metronidazole
Imipenem Cefuroxime
Antibiotics
Not reported
No
Not reported No
Not reported
No
Less Indication for Surgery
No Yes
Less Multiorgan Failure
No Not reported
Less Nonpancreatic lnfection
Yes Yes (not separated) Not reported Yes
Yes
Less Pancreatic lnfection
Infection
No
No
No Yes
Low Mortality Rate
Table 4. INTRAVENOUS ANTIBIOTIC PROPHYLAXIS IN SEVERE ACUTE PANCREATITIS: RESULTS OF CONTROLLED CLINICAL STUDIES
'Duration of treatment 4 days. t h r a t i o n of treatment 7 days.
Methods of AEP
Species
Authors
Table 3. INTRAVENOUS ANTIBIOTIC TREATMENT IN SEVERE ACUTE EXPERIMENTAL PANCREATITIS (AEP)
650
RATSCHKO et a1
modest spectrum of activity against gram-negative microorganisms, which are frequently seen in pancreatic infection. Second, ampicillin achieves poor penetration in pancreatic tissue5I and in pancreatic Third, given the low-risk disease in these studies,l6Z20, 26 they have insufficient statistical persuasion (type 2 e r r ~ r ) . ~ More recently, four studies have been published again addressing the question of the value of antibiotic prophylaxis in acute pancreatitis. In the study of Pederzoli et a1,40 74 patients with acute necrotizing pancreatitis, mostly of biliary origin, were enlisted. The Ranson score was 3.7 (mean value) and pancreatic necrosis had been proven by CT within 72 hours of onset. Patients were randomly assigned to two groups: one without antibiotic treatment and one receiving 0.5 g of imipenem every 8 hours for 2 weeks. The incidence of pancreatic sepsis was significantly reduced from 30.3% to 12.2% and that of nonpancreatic sepsis from 48.5% to 14.6% (P<.Ol). The incidence of multiorgan failure, the need for surgical treatment, and mortality rate were not influenced. Antibiotic prophylaxis was especially effective in patients with mild-tomoderate necrosis. None of the antibiotic groups with a pancreatic necrosis of less than 50% developed septic complications, in contrast to the control group. The study has been criticized for the unequal distribution of severe necrosis. Sixteen patients had severe necrosis (>50%), of whom 14 were in the treated and 2 in the nontreated group. This distribution may have prevented a statistically significant effect on the indication for surgery and on mortality and perhaps also on the development of multiorgan failure, although infected necrosis and multiorgan failure are not parallel events in acute pan~reatitis.~~ Sainio et a P reported on 60 patients with alcohol-induced necrotizing pancreatitis proven by contrast-enhanced CT within 24 hours of admission. The mean value for the Ranson score was 5.5. Thus, according to this prognostic score, these patients were more severely ill than those in the study of Pederzoli et a1.4O Thirty patients were assigned cefuroxime (1.5 g intravenously three times a day until clinical recovery and fall to normal of C-reactive protein concentrations), and 30 patients were assigned to a nonantibiotic group receiving no antibiotic treatment before infection had been clinically, microbiologically, or radiologically verified or until there was a second rise in C-reactive protein of more than 20% after the acute phase. In case of full clinical recovery in the antibiotic group and moderately C-reactive protein concentrations, antibiotic treatment was continued with cefuroxime by mouth (250 mg/ two times a day) for 14 days. Infectious complications were reduced from 1.8 in the nonantibiotic group to 1.0 in the antibiotic group (mean values, P = .01). When infectious complications were analyzed separately, only the difference in urinary tract infections was significantly reduced in the prophylactic group. The most common cause of infections was Staphylococcus epiderrnidis, which was also present in the cultures from pancreatic necrosis in four of eight patients who died from acute pancreatitis. Sainio’s study has been criticized because of the strikingly high
ANTIBIOTIC PROPHYLAXIS IN THE TREATMENT OF ACUTE PANCREATITIS
651
number of urinary tract infections and the high rate of S. epidermidis infections.8 Furthermore, concerning the choice of cefuroxime, tissue concentrations may have been suboptimal, and in 20 of 30 patients of the antibiotic group, antibiotic treatment had to be changed after a mean of 9.2 days. The authors had chosen cefuroxime because of the high frequency of Staphylococcus aureus infections in the intensive care unit patients and because E. coli, a common cause of infected pancreatic necrosis, is generally seldomly resistant to cefuroxime in hospitals. Another criticism is that S. qidermidis is not usually found in pancreatic necrosis infection, and the origin of this infection remains unclear.8 In a third study, Delcenserie et all7enlisted 23 patients with alcoholinduced acute pancreatitis with CT scans demonstrating two or more fluid collections within 48 hours of onset of symptoms and randomly assigned them to two groups: one receiving nonantibiotic treatment and one receiving prophylaxis antibiotics (ceftazidime, amikacin, and metronidazole for 10 days). Sepsis was diagnosed by positive cultures. Seven episodes of severe sepsis occurred (pancreatic infection and septic shock) in the control group, and no infection occurred in the prophylactic antibiotic group (R.03). Neither the incidence of multiple organ failure nor the mortality rate was significantly influenced. In the fourth study, Schwarz et a149investigated 26 patients with acute necrotizing pancreatitis, mostly of biliary origin, and sterile pancreatic necrosis as proven by contrast-enhanced CT and fine-needle aspiration. The patients were randomized into two groups: a control group (initially no antibiotics) and a group receiving twice daily intravenously 200 mg ofloxacin and 500 mg metronidazole. In both patient groups, fine-needle aspirations of the necrotic areas were performed on days 1, 3, 5, 7, and 10. When there was evidence of infection, antibiotics were then also given to patients of the control group. The extent of necrosis was the same-40% (median) for both groups. The necrosis became infected within a median of 9.5 and 10 days (treated and untreated group). The clinical course as documented by the APACHE I1 score should have significantly improved under antibiotic treatment, but antibiotic prophylaxis neither prevented nor delayed bacterial infection of the necrotic pancreas. Two of the control group but none of the treated group died within the first 3 weeks (statistical significance not given). Although in these four studies antibiotic prophylaxis was compared against placebo, in another study-available presently only as an abstractpefloxacin was tested against imipenem in 56 patients who suffered severe pancreatitis with an extensive necrosis involving greater than 50% of the gland. The patients received either pefloxacin 400 mg twice daily (n=27) or 500 mg imipenem three times daily. Ranson score was 4.6, and APACHE I1 score was 11.5 (over all mean values). The rates of infected necrosis and extrapancreatic infections were 37% versus 10.3% and 48% versus 20.6% (pefloxacin versus imipenem group; Pc.05). Death rates, all resulting from sepsis, were not significantly different (pefloxacin 18.5%, imipenem 10.3%).Thus, pefloxacin was not superior
652
RATSCHKO et a1
to imipenem in the prevention of infected necrosis during severe acute pancreatitis.6,6a Selective Gut Decontamination
Selective gut decontamination with oral antibiotics is an alternative strategy, aimed at eliminating pathogen intestinal flora to reduce bacterial translocation, thereby reducing the risk of pancreatic infection (Table 5).,, This approach was tested almost 50 years ago by Persky et aLM They used a duct model in dogs inducing acute pancreatitis by the injection of bile into the pancreatic duct. The mortality rate for this form of experimental pancreatitis was higher than 90%. Aureomycin, given orally for 5 to 10 days until coliform microorganisms were absent in the feces of the animals for 3 successive days, reduced the mortality rate to zero. In another experiment, aureomycin was given immediately after operation, but because many of the capsules had not dissolved, mortality was 75%. When aureomycin was suspended in water and given by gavage immediately after operation, mortality rate was again zero. In 'contrast, aureomycin given intravenously immediately postoperatively resulted in a survival rate of 40%.& These early important experiments, showing for the first time that gut decontamination is helpful in acute experimental pancreatitis, were forgotten for many decades until Lange et a1,32also using a duct model, induced acute experimental pancreatitis in the rat to study the effect of gut decontamination. Rats underwent either a subtotal colectomy or an intestinal lavage plus an infusion of kanamycin. Both procedures had a significant effect on the mortality rate, thus indicating that the intestinal flora was a major factor influencing mortality in this experimental Isaji et alZ7further studied the effect of bacterial infection in mice with diet-induced acute pancreatitis. Oral application of bacitracin, metronidazole, and neomycin increased survival rate significantly and reduced infection, although this outcome failed to reach the level of significance. Foitzik et alZ1studied different strategies of antibiotic treatment for the prevention of early pancreatic infection in an experimental model in which acute pancreatitis was induced by a combination of intraductal injection of a glycodeoxycholic acid in addition to intravenous cerulein hyperstimulation. Treatment was begun 6 hours after induction of acute pancreatitis. Mortality rate was unaffected by any treatment regimen, but pancreatic infection was significantly reduced by full gut decontamination and by imipenem, not by oral antibiotics or by cefotaxime alone. The authors reached the following conclusions: (1) Direct bacterial translocations from the gut and hematogenous seeding interact in pancreatic infection. (2) Hematogenous seeding is dominant at extrapancreatic sides. (3) Their conclusions hold true only with a full gut decontamination or an antibiotic concentrated on the pancreas (imipenem). (4) The
Rat
Mouse
Foitzik et a12'
Gianotti et alZ
Duct plus hyperstimulation model CDE model
Duct model Duct model CDE model
Methods of AEP
CDE = Choline-deficientethionine-supplemented diet.
Dog Rat Mouse
Species
Persky et al" Lange et a132 Isaji et a12'
Authors
Oral application of aureomycin Intestinal lavage plus canamycin Oral application of bactracinel, metronidazole, neomycin Oral application of polymyxin B, tobramycin, amphotericin B plus intravenous cefotaxime Various antibiotics
Method of Decontamination
6 h after AEP 36 h after beginning of CDE diet
Not studied Yes No
5-10 d before AEP Immediately before AEP Simultaneously with AEP 6 h after AEP
Yes Yes
Yes
Less Infedtion
Start of Decontamination
Table 5. ANTIBIOTIC DECONTAMINATION OF THE GUT IN ACUTE EXPERIMENTAL PANCREATITIS (AEP)
No No
No
Yes Yes Yes
Less Mortality Rate
654
RATSCHKO et a1
conclusions do not hold true in the case of unconcentrated antibiotics of similar spectrum (cefotaxime)or oral antibiotics alone. Gianotti et alZ3studied various antibiotics in mice, in which acute pancreatitis was again induced by a diet deficient in choline and supplemented with ethionine. Some effect on survival rate was seen early but not later on after polymyxin B, amikacin, and amphotericin B were administered. All antibiotics used reduced the number of bacteria in the cecum, but only some reduced the rate of translocation of gram-positive and gram-negative microorganisms to all organs. The only controlled clinical study of selective decontamination was performed in a multicenter trial by Luiten et a135in 102 patients with severe acute pancreatitis. Patients were randomly assigned to a standard treatment group or a group given standard treatment plus selective decontamination, which consisted of oral administration of colistin sulfate, amphotericin B, and norfloxacin every 6 hours via application of a sticky paste containing 2% of these three drugs smeared along the gums every 6 hours. In addition, a rectal enema was given every day containing all three antibiotics in the same dosage as the oral administration. This regimen was supplemented by a short-time systemic prophylaxis of cefotaxime, which was given every 8 hours until gram-negative microorganisms were eliminated from the oral cavity and rectum. Mortality rate was 35% in the control group and 22% in the group given selective decontamination ( P = .048). This difference was mainly caused by reduction of late mortality (>2 weeks) because of significant reduction of gram-negative pancreatic infection ( P = .003). Furthermore, the average number of laparotomies per patient was reduced in the group with selective decontamination ( P = .05), and gram-negative pancreatic infection was reduced from 33% to 8% ( P = .003). Further studies are required before this therapy can be recommended. CONCLUSIONS
Earlier studies on preventing pancreatic infection by use of antibiotic prophylaxis came to naught because later studies showed that the antibiotics used were inappropriate.lb,20, 26 In the meantime, considerable interest has been concentrated on antibiotics in pancreatic fluid and tissue in humans. Some controlled clinical studies have demonstrated benefits 40, 48, 49 All these from antibiotic prophylaxis in severe acute pan~reatitis.'~, studies, although prospective, were small, and the data were not uniform. The choice of antibiotic and the duration of therapy still remain debatable issues.29Powell et a145 have stated that assuming 30% of patients with prognostically severe acute pancreatitis develop infected pancreatic necrosis, a total sample size of 322 is required to detect a 50% reduction in the rate of infection, assuming a two-tailed test with a significance level of 5% and a study power of 90%. Even larger studies are required to evaluate reduction in the mortality rate.45Most clinicians nowadays, however, would hesitate to involve patients with severe acute
ANTIBIOTIC PROPHYLAXIS IN THE TREATMENT OF ACUTE PANCIEATITIS
655
pancreatitis in studies with a ”no-antibiotic arm”45and for ethical reasons would test different antibiotics only against one other.6 Current recommendations are not uniform. The American Society of Gastroenterology practice guidelines merely state that it is ”reasonable to initiate” antibiotic therapy in severe acute pan~reatitis.~ The United Kingdom guidelines for the management of acute pancreatitisZ4simply state that the place of antibiotics in severe acute pancreatitis is unclear. Strongly suspected or confirmed local infective complications (infected necrosis, pancreatic abscess, and infected fluid collections) require appropriate antibiotics in addition to formal drainage by percutaneous or surgical means. Prophylactic antibiotics are recommended before invasive procedures, such as ERCP and surgery. Finally, British workers state that there is a place for prophylactic antibiotics early in an attack of acute pancreatitis predicted as severe. Cefuroxime is currently the antibiotic recommended, but treatment duration is unclear.24The Spanish Consensus Conference concluded that all patients with acute pancreatitis and proven pancreatic necrosis should be treated for 2 weeks immediately after pancreatic necrosis is diagnosed by CT with imipenem 500 mg every 8 hours. If the patient remains critically ill, the duration of treatment may be extended.36The German Society of Gastroenterology in its consensus conference has stated that there is an indication for antibiotic prophylaxis in acute necrotizing pancreatitis (intrapancreatic and extrapancreatic necrosis) and in those patients with a severe course of the disease (multiorgan failure, C-reactive protein 2120 mg/L, Ranson score 23, APACHE I1 score 2 8 ) (in preparation), and this is also the authors’ recommendation. The duration of antibiotic treatment in necrotizing acute pancreatitis or the duration of an antibiotic prophylaxis depends on the course of the disease; antibiotic prophylaxis or treatment, however, should be given for not less than 7 to 10 days. Recommended antibiotics (Table 6 ) may be divided into antibiotics of first choice and those that represent a possible alternative. First-choice antibiotics are carbapenems, which combine the effect of broad-spectrum penicillins and broad-spectrum third-generation cephalosporins. Imipenem is a standard carbapenem with a strong activity against almost all gram-positive and gram-negative microorganisms, including anaerobics. At present, imipenem is the antibiotic with the broadest spectrum and the highest activity against aerobics. Imipenem is also an alternative for antibiotic combinations that are used as initial treatment in severe bacterial infections or polyinfections. Other first-choice antibiotics are the quinolones (ciprofloxacin, ofloxacin) in combination with metronidazole. Quinolones are highly active against gram-negative microorganisms, including Pseudomonas and Salmonella species, and-with few exceptions-are also effective against gram-positive microorganisms. The effect against anaerobics is insufficient; therefore, quinolones should be combined with metronidazole. Metronidazole is active against anaerobics (Bacteroidesfiagilis, Clostridium and anaerobic cocci).
m
m
m
Ureidopenicillins Cephalosporins (third generation) Quinolones
First choice Carbapenems Quinolones (second generation) Possible alternatives Cephalosporins (third generation)
Group
200400 mg
Ofloxacin IV X
2 times/d
2 times/d
100-200 mg
Ciprofloxacin IV X
500 mg X 2-3 times/d 300-600 mg X 3-4 times/d 300-600 mg X 3-4 times/d 300-600mg X 3 4 times/d
Metronidazole IV Lincomycins IV (clindamycin) Lincomycins IV (clindamycin) Lincomycins IV (clindamycin)
2-3 times/d 2-3 times/d
Mezlocillin Ceftazidime IV
X
X
500 mg 500 mg
Metronidazole IV Metronidazole IV
2-3 times/d 2-3 times/d
1-2 g x 2-3 times/d (up 3 g x 4 times/d) 1-2 g x 2-3 times/d 2-5 g X 3-4 times/d 1-2 g X 2-3 times/d
X X
Cefotaxime IV Ceftazidime IV
500 mg 500 mg
Dosage
Metronidazole IV Metronidazole IV
Combined With
0.5-1 g X 3-4 times/d 100-200 mg x 2 times/d 200-400 mg x 2 times/d
Dosage
Imipenem-cilastatin IV Ciprofloxacin IV Ofloxacin IV
Substance
Table 6. RECOMMENDED ANTIBIOTIC PROPHYLAXIS IN THE TREATMENT OF ACUTE PANCREATITIS
ANTIBIOTIC PROPHYLAXIS IN THE TREATMENT OF ACUTE PANCREATITIS
657
Possible alternatives are third-generation cephalosporins, ureidopenicillins, such as piperacillin, both in combination with metronidazolole, and third-generation cephalosporins and quinolones, both in combination with lincomycins. Cefotaxime, a third-generation cephalosporin, is more active than the second-generation cephalosporins against gramnegative microorganisms but less active against some gram-positive microorganisms. Cefotaxime should therefore be given in cases of severe infection caused by gram-negative microorganisms and in combination with metronidazole against gram-positive microorganisms. Ceftazidime has a similar spectrum but is, in addition, highly effective against Pseudomonas species. When staphylococci or anaerobics are suspected, ceftazidime can be combined with lincomycins (clindamycin). The main indication of mezlocillin, a broad-spectrum ureidopenicillin, is severe infection by gram-negative microorganisms, usually coming from bile ducts or the urogenital tract. A combination with metronidazole may be helpful. Clindamycin is an important antibiotic against severe infections, including anaerobic microorganisms such as staphylococci. When combined with third-generation cephalosporins and quinolones, it is especially helpful against staphylococci and anaerobic microorganisms. An additional primary prophylaxis against fungi during an antibiotic treatment or a selective gut decontamination is not recommended at the present time.
References 1. Araida T, Frey CF, Ruebner B, et al: Therapeutic regimens in acute experimental pancreatitis in rats: Effects of a protease inhibitor, a P-agonist, and antibiotics. Pancreas 11:132, 1995 2. Banks PA: Acute pancreatitis: Medical and surgical management. Am J Gastroenterol 89:S78, 1994 3. Banks PA: Practice guidelines in acute pancreatitis. Am J Gastroenterol92:377, 1997 4. Banks PA, Gerzof SG, Langevin RE, et al: CT-guided aspiration of suspected pancreatic infection: Bacteriology and clinical outcome. Int J Pancreatol 18265, 1995 5. Barie P S A critical review of antibiotic prophylaxis in severe acute pancreatitis. Am J Surg 172(suppl6A):38S, 1996 6. Bassi C, Falconi M, Talamini G, et al: Results of a multicenter clinical trial of pefloxacin versus imipenem in severe pancreatitis [abstr]. Gastroenterology 114A1378, 1998 6a. Bassi C, Falconi M, Talamini G, et al: Controlled clinical trial of pefloxacin versus imipenem in severe acute pancreatitis. Gastroenterology 115:1513, 1998 7. Bassi C, Pederzoli P, Vesentini S, et al: Behavior of antibiotics during human necrotizing pancreatitis. Antimicrob Agents Chemother 38:830, 1994 8. Baudin F, Ozier Y Early antibiotic treatment in acute necrotising pancreatitis. Lancet 346:1374, 1995 9. Beger HG, Bittner R, Block S, et al: Bacterial contamination of pancreatic necrosis: A prospective clinical study. Gastroenterology 91:433, 1986 10. Benveniste GL, Morris RG: Penetration of cefotaxime into pancreatic juice. Lancet 1:588, 1985 11. Bittner R, Block S, Buchler M, et al: Pancreatic abscess and infected pancreatic necrosis: Different local septic complications in acute pancreatitis. Dig Dis Sci 321082, 1987 12. Bradley I11 EL: A clinically based classification system for acute pancreatitis. Summary
658
RATSCHKO et a1
of the International Symposium on Acute Pancreatitis, Atlanta, GA, September 11 through 13, 1992. Arch Surg 128:586, 1993 13. Bradley I11 EL: A fifteen year experience with open drainage for infected pancreatic necrosis. Surg Gynecol Obstet 177215, 1993 14. Brattstrom C, Malmborg A-S, TydCn G: Penetration of clindamycin, cefoxitin, and piperacillin into pancreatic juice in man. Surgery 103:563, 1988 15. Buchler M, Malfertheiner P, Friess H, et a1 Human pancreatic tissue concentration of bactericidal antibiotics. Gastroenterology 103:1902, 1692 16. Craig RM, Dordal E, Myles L The use of ampicillin in acute pancreatitis. AM Intem Med 83:831, 1975 17. Delcenserie R, Yzet T, Ducroix JP: Prophylactic antibiotics in treatment of severe acute alcoholic pancreatitis. Pancreas 13:198, 1996 18. Drewelow B, Koch K, Otto C, et al: Penetration of ceftazidime into human pancreas. Infection 21:229, 1993 19. Fedorak IJ, KO TC, Dpricin G, et a1 Secondary pancreatic infections: Are they distinct clinical entities? Surgery 112:824, 1992 20. Finch WT, Sawyers JL, Schenker S: A prospective study to determine the efficacy of antibiotics in acute pancreatitis. Ann Surg 183:667, 1976 21. Foitzik T, Fernhdez-del Castillo C, Ferraro MJ, et al: Pathogenesis and prevention of early pancreatic infection in experimental acute necrotizing pancreatitis. AM Surg 222:179, 1995 22. Gerzof SG, Banks PA, Robbins AH, et al: Early diagnosis of pancreatic infection by computed tomography-guided aspiration. Gastroenterology 93:1315, 1987 23. Gianotti L, Munda R, Gennari R, et al: Effect of different regimens of gut decontamination on bacterial translocation and mortality in experimental acute pancreatitis. Eur J Surg 161:85, 1995 24. Glazer G, Mann DV: United Kingdom guidelines for the management of acute pancreatitis. Gut 42(suppl 2):Sl-S13, 1998 25. Gregg JA, Maher L, DeGirolami PC, et al: Secretion of p-lactam antibiotics in pure human pancreatic juice. Am J Surg 150:333, 1985 26. Howes R, Zuidema GD, Cameron JL: Evaluation of prophylactic antibiotics in acute pancreatitis. J Surg Res 18:197, 197.5 27. Isaji S, Suzuki M, Frey CF, et al: Role of bacterial infection in diet-induced acute pancreatitis in mice. Int J Pancreatol 11:49, 1992 28. Isenmann R, Buchler MW Infection and acute pancreatitis. Br J Surg 81:1707, 1994 29. Johnson C D Antibiotic prophylaxis in severe acute pancreatitis. Br J Surg 83:883, 1996 30. Koch K, Drewelow B, Brinckmann W Die Pankreaspenetration von Ofloxacin-Eine Pilotstudie. Z Gastroenterol 31:587, 1993 31. Koch K, Drewelow 8, Liebe S, et al: Die Pankreasgangigkeit von Antibiotica. Chirurg 62:317, 1991 32. Lange JF, van Cool J, Tytgat GNJ: The protective effect of a reduction in intestinal flora on mortality of acute haemorrhagic pancreatitis in the rat. Hepatogastroenterology 3428, 1987 33. Lankisch PG, Banks PA: Pancreatitis. Berlin, Springer 1998 34. Lankisch PG, Klesel N, Seeger K, et al: Penetration of cefotaxime into the pancreas. Z Gastroenterol 21:601, 1983 35. Luiten EJT, Hop WCJ, Lange JF, et al: Controlled clinical trial of selective decontamination for the treatment of severe acute pancreatitis. Ann Surg 222:57,1995 36. Martinez JF, Palazon JM, Perez-Mateo M: Antibioterapia profillctica en pancreatitis aguda: Resultados de una conferencia de consenso. Rev Esp Enf Digest 89:781, 1997 37. McFadden DW, Reber HA: Indications for surgery in severe acute pancreatitis. Int J Pancreatol 15:83, 1994 38. Mithofer F, Femandez-del Castillo C, Ferraro MJ, et al: Antibiotic treatment improves survival in experimental acute necrotizing pancreatitis. Gastroenterology 110:232, 1996 39. Moody FG, Haley-Russell D, Muncy DM: Intestinal transit and bacterial translocation in obstructive pancreatitis. Dig Dis Sci 40:1798,1995 40. Pederzoli P, Bassi C, Vesentini S, et al: A randomized multicenter clinical trial of
ANTIBIOTIC PROPHYLAXISIN THE TREATMENT OF ACUTE PANCREATITIS
659
antibiotic prophylaxis of septic complications in acute necrotizing pancreatitis with imipenem. Surg Gynecol Obstet 176:480, 1993 41. Pederzoli P, Falconi M, Bassi C, et al: Ofloxacin penetration into bile and pancreatic juice. J Antimicrob Chemother 23:805, 1989 42. Pederzoli P, Falconi M, Bassi C, et a1 Ciprofloxacin penetration in pancreatic juice. Chemotherapy 33397,1987 43. Pederzoli P, Orcalli F, Falconi M, et al: Penetration of mezlocillin into pancreatic juice. J Antimicrob Chemother 17397, 1986 44. Persky L, Schweinburg FB, Jacob S, et al: Aureomycin in experimental acute pancreatitis of dogs. Surgery 30:652,1951 45. Powell JJ, Miles R, Sirivardena AK Antibiotic prophylaxis in the initial management of severe acute pancreatitis. Br J Surg 85:582, 1998 46. Roberts EA, Williams RJ: Ampicillin concentrations in pancreatic fluid bile obtained at endoscopic retrograde chohgiopancreatography (ERCP). Scand J Gastroenterol 14:669. 1979 47. Runkel NSF, Moody FG, Smith GS, et al: The role of the gut in the development of sepsis in acute pancreatitis. J Surg Res 51:18, 1991 48. Sainio V, Kemppainen E, Puolakkainen P, et al: Early antibiotic treatment in acute necrotising pancreatitis. Lancet 346:663, 1995 49. Schwarz M, Isenmann R, Meyer H, et al: Antibiotika bei nekrotisierender Pankreatitis: Ergebnisse einer kontrollierten Studie. Dtsch Med Wochenschr 122:356, 1997 50. Tenner S, Sica G, Hughes M, et al: Relationship of necrosis to organ failure in severe acute pancreatitis. Gastroenterology 113:899, 1997 51. Trudel JL, Wittnich C, Brown RA: Antibiotics bioavailability in acute experimental pancreatitis. J Am Coll Surg 178475, 1994 52. Widdison AL, Karanjia ND, Reber HA: Antimicrobial treatment of pancreatic infection in cats. Br J Surg 81:886, 1994
Address reprint requests to Paul Georg Lankisch, MD Medizinische Klinik Stadtisches Klinikum Boegelstrasse 1 D-21339 Liineburg Germany
0889-8553/99 $8.00
+ .OO
THE .ROLE OF ANTIBIOTIC PROPHYLAXIS IN THE TREATMENT OF ACUTE PANCREATITIS Manfred Ratschko, Thomas Fenner, MD, and Paul Georg Lankisch, MD
Infection of the pancreas has been a dreaded complication of acute pancreatitis for many years.33Before the availability of computed tomography (CT), patients with severe pancreatitis were treated for at least 4 to 6 weeks before surgery was resorted to as a last life-saving effort in seriously ill, nearly moribund patients. In most of these patients, pancreatic necrosis involved infections, and the patient invariably required several relaparotomies for d6bridement of residual infected tissue. Mortality generally exceeded 50%. The situation has now changed with the availability of contrast-enhanced CT in most centers and ultrasoundguided or CT-guided aspiration of pancreatic necrosis for diagnosing pancreatic infection. Both procedures constitute the gold standards for detecting pancreatic necrosis and infection, thus enabling surgeons to perform pancreatic d6bridement at an earlier stage in patients with infected pancreatic necrosis or sterile necrosis with persistence of systemic These detection methods raised the question of whether an antibiotic could or should be administered prophylactically to improve the clinical course and patient survival rate. The question has led to considerable controversy5,28, 45 Johnsonz9reviewed experimental and clinical
From the Central Pharmacy (MR), and the Department of Medicine (PGL), Municipal Clinic of Liineburg, Liineburg; and the Institute for Clinical Pathology and Microbiology (TF), Hamburg, Germany GASTROENTEROLOGY CLINICS OF NORTH AMERICA
-
VOLUME 28 NUMBER 3 SEPTEMBER 1999
641
642
RATSCHKO et a1
studies relating to antibiotic prophylaxis in acute pancreatitis. The authors critically review available data and review the approach to this frequent clinical debate. INFECTION IN ACUTE PANCREATITIS
It is difficult to estimate the prevalence of pancreatic infection because most reports are from tertiary referral centers with a vested interest in the disease. Acute interstitial pancreatitis is estimated to occur in approximately 80% of acute pancreatitis cases and necrotizing pancreatitis in the remaining 20%. Infection in necrotizing pancreatitis occurs in 40% and is either a spreading infection of devitalized tissue in the retroperitoneum (infected necrosis) or a localized abscess.", 12, l9 Infections develop within the first 2 weeks of illness after admission to the hospital, which is usually shortly after onset of symptoms, in approximately 50% of necrotizing pancreatitis cases, and in 71%, infections develop within the first 3 weeks of illne~s.~, 22 A pancreatic abscess has not been detected before the first month of illness11,19 and thus is a later onset than infected necrosis. Although the gold standard for diagnosing pancreatic necrosis is the dynamic contrast-enhanced CT scan, this procedure is not helpful for diagnosing infection. The only signs of infection that can be detected are air bubbles in and around pancreatic necrosis. Otherwise, there is no particular feature on contrast-enhanced CT that permits distinguishing infected from sterile necrosis. Clinically, pancreatic infection may be suspected on the basis of unresolved organ failure, persisting systemic toxicity, or both. In this case, ultrasound-guided or CT-guided percutaneous aspiration of suspected pancreatic tissue with bacteriologic sampling should be performed. Needle aspirates should be obtained from areas of necrosis using a 20- to 22-gauge needle via a route that avoids the colon. Because of the importance of not transgressing the colon and thereby risking inoculation of colonic flora into the retroperitoneum, it is recommended that patients receive oral contrast agents routinely to opacify the colon when the aspiration is CT guided. Fluid obtained should be carried by hand immediately to the bacteriology laboratory for Gram staining and culture (for aerobic and anaerobic bacteria and fungi).33Gram stain has proven to be reliable as an early indicator of pancreatic infection. In one retrospective study, there was no instance of a positive Gram staining followed by a negative culture, and in almost all cases of a positive culture, the Gram stain also revealed organism^.^ The fact that colonic-type bacteria frequently cause pancreatic infection has led to the theory that the gut acts as a reservoir from which bacteria can translocate to colonize pancreatic necrosis and acute fluid collections resulting in infected pancreatic necrosis and pancreatic abs c e ~ s e sThere . ~ ~ is supporting evidence for this in experimental studies39, 47,52 showing that bacteria are able to reach the gland from the colon by direct transmural spread. Once infections are identified, appropriate
ANTIBIOTIC PROPHYLAXIS IN THE TREATMENT OF ACUTE PANCREATITIS
643
antibiotics should be prescribed. Infected necrosis is usually treated by prompt surgical dkbridement? 37 whereas an abscess may be treated either by a pigtail catheter drainage or by surgical drainage.2,11, l9 Although using antibiotic treatment in the case of proven infection raises no questions, there is considerable discussion concerning antibiotic prophylaxis in acute pancreatitis. Some studies have reported the incidence of microorganism-associated secondary infection in patients with pancreatic infection, infected necrosis, abscess, or pseudocyst (Table 1). It appears that the data concerning monomicrobial and polymicrobial infections are not uniform. Further studies are required. Currently, it seems that in cases of pancreatic abscess, polymicrobial infections are more frequent.l’,l9 Among gram-negative aerobic microorganisms, Escherichia coli and other enterobacteriaceae are most frequent, whereas among the gram-positive aerobic microorganisms, staphylococci and enterococci are the most frequent. Anaerobic and fungal infections are uncommon, but it is believed that an increased usage of antibiotics may spark the prevalence of the PENETRABILITY OF ANTIBIOTICS INTO HUMAN PANCREATIC FLUID AND TISSUE
To select antibiotics for the treatment of acute pancreatitis or for the prophylaxis of pancreatic infection, the clinician needs to know whether the antibiotics are able to penetrate into human pancreatic fluid or pancreatic tissue. Because of possibly divergent results obtained in animal experiments and human studies, only human studies were tabulated for reviewing penetrability of antibiotics (Table 2). At present, there are 13 studies showing the effect of antibiotics on the human pancreas, and they differ considerably.* In most studies, the parenteral route of administration for the antibiotics was used, which is appropriate for a patient with acute pancreatitis. Eight studies measured the penetrability of the antibiotic into pancreatic fluid, obtained either on endoscopic retrograde cholangiopancreatography (ERCP) or after stimulation of the 14, ~ 531, , 46 In one studyMthe content of pseudocysts pancreatic fistula.lO, was used to test the penetration of the antibiotic. In the remaining studies, antibiotic contents were looked for in pancreatic tissue. Tissue samples were obtained from patients with different pancreatic diseases and different degrees of inflammation (acute pancreatitis, chronic pancreatitis, pancreatic carcinoma). Human studies15 have shown that the antibiotic level depends on the degree of inflammation, and thus the levels are higher in acute pancreatitis as compared to controls. The authors, listed in the order of date of publication, reported the following results: 41437
Roberts and Williams46failed to detect in pancreatic fluid obtained on *References 7, 10, 14, 15, 18, 25, 30, 31, 34, 4143, 46
BradleyI3 Banks et a14
Fedorak et all9
Berger et a19 Gerzof **
Authors
Pancreatic abscess Infected pseudocyst Infected necrosis Pancreatic infection
Infected necrosis Pancreatic infection Infected necrosis
Nature of Pancreatic Complication
-
53 86
40 78 47 14
60 22
57
-
-
43
Polymicrobial Infections (%)
Monomicrobial Infection (%)
~
47 21
30 35
24
53 24
(%)
E. coli
10 4
20 0
14
5
11
(%)
Pseudomonas
14 35
60 26
34
56 45
(%)
Other Enerobacteriaceae
Gram-Negative Microorganisms ~
2 22
30 17
57
11 12
3 14
40 13
33
13 24
(%)
Enterococci
Gram-Positive Microorganisms Staphylococci(%)
Table 1. MICROORGANISMS ASSOCIATED WITH SECONDARY INFECTION IN ACUTE PANCREATITIS
6 4
-
4
5 9
19
7 -
(%I
Fungi
15 4
9
11 7
Anaerobes (%)
ANTIBIOTIC PROPHYLAXIS IN THE TREATMENT OF ACUTE PANCREATITIS
645
ERCP the antibiotic ampicillin, which was used in the first studies evaluating antibiotics in human acute pancreatitis.l6,20, 26 Benveniste and Morrisloand Lankisch et a134reported sufficient bactericidal concentrations of cefotaxime in both pancreatic juice and pancreatic pseudocysts. Gregg et alZ5tested cephalothin and cefoxitin and failed to find them in pure pancreatic juice obtained from patients with acute relapsing and chronic pancreatitis and controls. Pederzoli et a1 found in pancreatic fluid sufficiently bactericidal concentrations of mez10cillin,4~ciprofloxacin," and ofloxacin.4l Brattstrom et all4 reported only sufficient bactericidal concentrations for clindamycin but not for cefoxitin and piperacillin in patients with pancreas transplants. Koch et a131tested ampicillin, azlocillin, mezlocillin, cefotiam, gentamicin, doxycycline, chloramphenicol, metronidazole, and ciprofloxacin and found sufficient bactericidal concentrations of mezlocillin, ciprofloxacin, metronidazole, doxycycline, and chloramphenicol. Buchler et all5 tested mezlocillin, piperacillin, cefotaxime, ceftizoxime, netilmicin, tobramycin, ofloxacin, ciprofloxacin, imipenem, and metronidazole in patients who underwent pancreatic surgery for acute or chronic pancreatitis or pancreatic carcinoma. Based on the detection of the antibiotics in the pancreatic tissue, three groups of antibiotics were established: group A, substances with low tissue concentrations (netilmicin, tobramycin) that were below the minimal inhibitory concentrations of most bacteria found in pancreatic infection; group B, antibiotics with pancreatic tissue concentrations that were sufficient to inhibit some, but not all, bacteria in pancreatic infection (mezlocillin, piperacillin, ceftizoxime, cefotaxime); and group C, substances with high pancreatic tissue levels as well as high bactericidal activity against most of the germs present in pancreatic infection (ciprofloxacin,ofloxacin, imipenem-cilastatin). The group of Drewelow and Koch18,30 found sufficient bactericidal concentrations of ceftazidime and ofloxacin in pancreatic tissue of patients with a variety of pancreatic diseases. Bassi et a17 tested the penetration of imipenem, mezlocillin, gentamicin, amikacin, pefloxacin, and metronidazole in cases of pancreatic necrosis. Samples were obtained by fine-needle aspiration or during operation or surgical drainage. Gentamicin and amikacin were not detected, whereas the others were found in sufficient bactericidal concentrations. A sufficiently high detection in pancreatic tissue or fluid was found for mezlocillin from the group of penicillins, third-generation cephalosporins, imipenem-cilastatin from the carbapenems group; quinolones, clindamycin, metronidazole, chloramphenicol, and doxycycline. The last two antibiotics, however, should not be used because of the high incidence of serious side effects. The other penicillins as well as firstgeneration and second-generation cephalosporins and aminoglycosides
P-Lactam antibiotics Penicillins Ampicillin Azlocillin Mezlocillin Piperacillin First-generation cephalosporins Cephalothin Second-generationcephalosporins Cefotiam Cefoxitin Third-generation cephalosporins Cefotaxime Ceftazidime Ceftizoxime Carbapenems Imiuenem-cilastatin
Class
+ + + +
+ ?
- 31 - 14, 25
-25
+
+ +
l5
+7
+
15
15
+
+
+ +
+
+
+ 7. 15
+ 31,43 -
-
-
-
15
15
Is
15
15
15
Pancreatic Carcinoma
-
+
+
Chronic Pancreatitis
- 31
Acute Pancreatitis
Detection in Pancreatic Tissue
- 31.34
Detection in Fluid
- 14
-
Oral
+
+ + +
Parenteral
Route of Administration
Table 2. PENETRABILITY OF ANTIBIOTICS INTO HUMAN PANCREATIC JUICE* AND TlSSUEt
Pseudocyst
+ + + + + +
+ + 14
+ 31
+ 31
+
30
+ 7. 15
+7
+
?
-
+ 41
+ 31, 42
+ 15
?
- 15 + 15.30
?
30
- 15
+
*Obtained during endoscopic retrograde cholangiopancreatography or via a pancreatic fistula. tOnly antibiotics tested in the different classes are mentioned. + = Antibiotic detected in sufficiently bactericidal concentration; - = antibiotic not detected or in insufficient bactericidal concentrations.
Other antibiotics Aminoglycosides Amikacin Gentamicin Netilmicin Tobramycin Chloramphenicol Quinolones Ciprofloxacin Ofloxacin Pefloxacin Lincom ycin s Clindamycin Nitroimidazole Metronidazole Tetracyclines Doxycycline ?
?
-
were not found in sufficient amounts in pancreatic fluid or tissue and thus are not helpful in the prophylaxis or treatment of pancreatic infection. ANTIBIOTIC TREATMENT IN SEVERE ACUTE PANCREATITIS: EXPERIMENTAL STUDIES
There are not many experimental studies investigating the effect of prophylactic antibiotics on the prevention of pancreatic infection in acute pancreatitis (Table 3). Widdison et a152studied the effect of cefotaxime applied 12 hours after induction of acute experimental pancreatitis using a perfusion model in cats. They found that cefotaxime reached bactericidal levels in pancreatic tissue and juice and significantly prevented pancreatic infection. Araida et all studied the effect of piperacillin given immediately after induction of acute experimental pancreatitis in the rat (duct model) and found a positive effect both on the infection and or the survival rate. Foitzik et alZ1studied the effect of intravenously applied cefotaxime and imipenem plus the effect of full gut decontamination in a duct hyperstimulation model in the rat. Neither treatment had a positive effect on survival rate, but pancreatic bacterial counts were significantly reduced by imipenem, although not by cefotaxime. Mithofer et a1,38from the same group, used the same model to investigate the effect of imipenem and ciprofloxacin, but in their study the antibiotic treatment was given for 7 days instead of 4 days only. The prolongation of treatment is probably the reason for a positive effect of imipenem on survival rate in this study. Survival rate was also increased by ciprofloxacin. Both antibiotics reduced early and late septic pancreatic complications. ANTIBIOTIC PROPHYLAXIS IN SEVERE ACUTE PANCREATITIS Intravenous Application
Intravenous antibiotic prophylaxis in acute pancreatitis is based on the belief that adequate pancreatic tissue levels of antibiotics can prevent colonization of the inflamed pancreas after translocation of organisms from the gut (Table 4).45Three studies were published in the 1970s in which ampicillin or placebo was randomly given to less than 200 patients with acute pancreatitis, in most cases resulting from alcohol abuse. Only 1 patient of all studies died, and 26 had infectious complications. All studies agreed that ampicillin had no beneficial influence on the clinical *Or 26 For many course of the disease or on serum enyzme elevations.l6< years, this conclusion led to the erroneous impression that antibiotic prophylaxis was of no benefit in pancreatitis. These studies are now recognized to be flawed for several reasons. First, ampicillin has a
rD
Perfusion model Duct model Duct plus hyperstimulation model Duct plus hyperstimulation model
Cat Rat Rat
Rat
Widdison et aP2 Araida et al' Foitzik et alzl
Mithofer et a P
Imipenem Ciprofloxacin
Cefotaxime Piperacillin Imipenem Cefotaxime
Antibiotics
6 h after AEP
12 h after AEP Immediately after AEP 6 h after AEP
Start of Treatment
Positive effect Positive effect
Yes Yes Positive effect No effect
Less Infection
Yest Yes
Not studied Yes No' Yes
Lower Mortality Rate
Biliary Alcohol
Alcohol
Biliary
74 30
23
26
Authors
Pederzoli et a14" Sainio et a14*
Delcenserie et all7
Schwarz et a149
Dominating Cause of Acute Pancreatitis
Patients (n)
Ceftazidime, amikacin, metronidazole Ofloxacin plus metronidazole
Imipenem Cefuroxime
Antibiotics
Not reported
No
Not reported No
Not reported
No
Less Indication for Surgery
No Yes
Less Multiorgan Failure
No Not reported
Less Nonpancreatic lnfection
Yes Yes (not separated) Not reported Yes
Yes
Less Pancreatic lnfection
Infection
No
No
No Yes
Low Mortality Rate
Table 4. INTRAVENOUS ANTIBIOTIC PROPHYLAXIS IN SEVERE ACUTE PANCREATITIS: RESULTS OF CONTROLLED CLINICAL STUDIES
'Duration of treatment 4 days. t h r a t i o n of treatment 7 days.
Methods of AEP
Species
Authors
Table 3. INTRAVENOUS ANTIBIOTIC TREATMENT IN SEVERE ACUTE EXPERIMENTAL PANCREATITIS (AEP)
650
RATSCHKO et a1
modest spectrum of activity against gram-negative microorganisms, which are frequently seen in pancreatic infection. Second, ampicillin achieves poor penetration in pancreatic tissue5I and in pancreatic Third, given the low-risk disease in these studies,l6Z20, 26 they have insufficient statistical persuasion (type 2 e r r ~ r ) . ~ More recently, four studies have been published again addressing the question of the value of antibiotic prophylaxis in acute pancreatitis. In the study of Pederzoli et a1,40 74 patients with acute necrotizing pancreatitis, mostly of biliary origin, were enlisted. The Ranson score was 3.7 (mean value) and pancreatic necrosis had been proven by CT within 72 hours of onset. Patients were randomly assigned to two groups: one without antibiotic treatment and one receiving 0.5 g of imipenem every 8 hours for 2 weeks. The incidence of pancreatic sepsis was significantly reduced from 30.3% to 12.2% and that of nonpancreatic sepsis from 48.5% to 14.6% (P<.Ol). The incidence of multiorgan failure, the need for surgical treatment, and mortality rate were not influenced. Antibiotic prophylaxis was especially effective in patients with mild-tomoderate necrosis. None of the antibiotic groups with a pancreatic necrosis of less than 50% developed septic complications, in contrast to the control group. The study has been criticized for the unequal distribution of severe necrosis. Sixteen patients had severe necrosis (>50%), of whom 14 were in the treated and 2 in the nontreated group. This distribution may have prevented a statistically significant effect on the indication for surgery and on mortality and perhaps also on the development of multiorgan failure, although infected necrosis and multiorgan failure are not parallel events in acute pan~reatitis.~~ Sainio et a P reported on 60 patients with alcohol-induced necrotizing pancreatitis proven by contrast-enhanced CT within 24 hours of admission. The mean value for the Ranson score was 5.5. Thus, according to this prognostic score, these patients were more severely ill than those in the study of Pederzoli et a1.4O Thirty patients were assigned cefuroxime (1.5 g intravenously three times a day until clinical recovery and fall to normal of C-reactive protein concentrations), and 30 patients were assigned to a nonantibiotic group receiving no antibiotic treatment before infection had been clinically, microbiologically, or radiologically verified or until there was a second rise in C-reactive protein of more than 20% after the acute phase. In case of full clinical recovery in the antibiotic group and moderately C-reactive protein concentrations, antibiotic treatment was continued with cefuroxime by mouth (250 mg/ two times a day) for 14 days. Infectious complications were reduced from 1.8 in the nonantibiotic group to 1.0 in the antibiotic group (mean values, P = .01). When infectious complications were analyzed separately, only the difference in urinary tract infections was significantly reduced in the prophylactic group. The most common cause of infections was Staphylococcus epiderrnidis, which was also present in the cultures from pancreatic necrosis in four of eight patients who died from acute pancreatitis. Sainio’s study has been criticized because of the strikingly high
ANTIBIOTIC PROPHYLAXIS IN THE TREATMENT OF ACUTE PANCREATITIS
651
number of urinary tract infections and the high rate of S. epidermidis infections.8 Furthermore, concerning the choice of cefuroxime, tissue concentrations may have been suboptimal, and in 20 of 30 patients of the antibiotic group, antibiotic treatment had to be changed after a mean of 9.2 days. The authors had chosen cefuroxime because of the high frequency of Staphylococcus aureus infections in the intensive care unit patients and because E. coli, a common cause of infected pancreatic necrosis, is generally seldomly resistant to cefuroxime in hospitals. Another criticism is that S. qidermidis is not usually found in pancreatic necrosis infection, and the origin of this infection remains unclear.8 In a third study, Delcenserie et all7enlisted 23 patients with alcoholinduced acute pancreatitis with CT scans demonstrating two or more fluid collections within 48 hours of onset of symptoms and randomly assigned them to two groups: one receiving nonantibiotic treatment and one receiving prophylaxis antibiotics (ceftazidime, amikacin, and metronidazole for 10 days). Sepsis was diagnosed by positive cultures. Seven episodes of severe sepsis occurred (pancreatic infection and septic shock) in the control group, and no infection occurred in the prophylactic antibiotic group (R.03). Neither the incidence of multiple organ failure nor the mortality rate was significantly influenced. In the fourth study, Schwarz et a149investigated 26 patients with acute necrotizing pancreatitis, mostly of biliary origin, and sterile pancreatic necrosis as proven by contrast-enhanced CT and fine-needle aspiration. The patients were randomized into two groups: a control group (initially no antibiotics) and a group receiving twice daily intravenously 200 mg ofloxacin and 500 mg metronidazole. In both patient groups, fine-needle aspirations of the necrotic areas were performed on days 1, 3, 5, 7, and 10. When there was evidence of infection, antibiotics were then also given to patients of the control group. The extent of necrosis was the same-40% (median) for both groups. The necrosis became infected within a median of 9.5 and 10 days (treated and untreated group). The clinical course as documented by the APACHE I1 score should have significantly improved under antibiotic treatment, but antibiotic prophylaxis neither prevented nor delayed bacterial infection of the necrotic pancreas. Two of the control group but none of the treated group died within the first 3 weeks (statistical significance not given). Although in these four studies antibiotic prophylaxis was compared against placebo, in another study-available presently only as an abstractpefloxacin was tested against imipenem in 56 patients who suffered severe pancreatitis with an extensive necrosis involving greater than 50% of the gland. The patients received either pefloxacin 400 mg twice daily (n=27) or 500 mg imipenem three times daily. Ranson score was 4.6, and APACHE I1 score was 11.5 (over all mean values). The rates of infected necrosis and extrapancreatic infections were 37% versus 10.3% and 48% versus 20.6% (pefloxacin versus imipenem group; Pc.05). Death rates, all resulting from sepsis, were not significantly different (pefloxacin 18.5%, imipenem 10.3%).Thus, pefloxacin was not superior
652
RATSCHKO et a1
to imipenem in the prevention of infected necrosis during severe acute pancreatitis.6,6a Selective Gut Decontamination
Selective gut decontamination with oral antibiotics is an alternative strategy, aimed at eliminating pathogen intestinal flora to reduce bacterial translocation, thereby reducing the risk of pancreatic infection (Table 5).,, This approach was tested almost 50 years ago by Persky et aLM They used a duct model in dogs inducing acute pancreatitis by the injection of bile into the pancreatic duct. The mortality rate for this form of experimental pancreatitis was higher than 90%. Aureomycin, given orally for 5 to 10 days until coliform microorganisms were absent in the feces of the animals for 3 successive days, reduced the mortality rate to zero. In another experiment, aureomycin was given immediately after operation, but because many of the capsules had not dissolved, mortality was 75%. When aureomycin was suspended in water and given by gavage immediately after operation, mortality rate was again zero. In 'contrast, aureomycin given intravenously immediately postoperatively resulted in a survival rate of 40%.& These early important experiments, showing for the first time that gut decontamination is helpful in acute experimental pancreatitis, were forgotten for many decades until Lange et a1,32also using a duct model, induced acute experimental pancreatitis in the rat to study the effect of gut decontamination. Rats underwent either a subtotal colectomy or an intestinal lavage plus an infusion of kanamycin. Both procedures had a significant effect on the mortality rate, thus indicating that the intestinal flora was a major factor influencing mortality in this experimental Isaji et alZ7further studied the effect of bacterial infection in mice with diet-induced acute pancreatitis. Oral application of bacitracin, metronidazole, and neomycin increased survival rate significantly and reduced infection, although this outcome failed to reach the level of significance. Foitzik et alZ1studied different strategies of antibiotic treatment for the prevention of early pancreatic infection in an experimental model in which acute pancreatitis was induced by a combination of intraductal injection of a glycodeoxycholic acid in addition to intravenous cerulein hyperstimulation. Treatment was begun 6 hours after induction of acute pancreatitis. Mortality rate was unaffected by any treatment regimen, but pancreatic infection was significantly reduced by full gut decontamination and by imipenem, not by oral antibiotics or by cefotaxime alone. The authors reached the following conclusions: (1) Direct bacterial translocations from the gut and hematogenous seeding interact in pancreatic infection. (2) Hematogenous seeding is dominant at extrapancreatic sides. (3) Their conclusions hold true only with a full gut decontamination or an antibiotic concentrated on the pancreas (imipenem). (4) The
Rat
Mouse
Foitzik et a12'
Gianotti et alZ
Duct plus hyperstimulation model CDE model
Duct model Duct model CDE model
Methods of AEP
CDE = Choline-deficientethionine-supplemented diet.
Dog Rat Mouse
Species
Persky et al" Lange et a132 Isaji et a12'
Authors
Oral application of aureomycin Intestinal lavage plus canamycin Oral application of bactracinel, metronidazole, neomycin Oral application of polymyxin B, tobramycin, amphotericin B plus intravenous cefotaxime Various antibiotics
Method of Decontamination
6 h after AEP 36 h after beginning of CDE diet
Not studied Yes No
5-10 d before AEP Immediately before AEP Simultaneously with AEP 6 h after AEP
Yes Yes
Yes
Less Infedtion
Start of Decontamination
Table 5. ANTIBIOTIC DECONTAMINATION OF THE GUT IN ACUTE EXPERIMENTAL PANCREATITIS (AEP)
No No
No
Yes Yes Yes
Less Mortality Rate
654
RATSCHKO et a1
conclusions do not hold true in the case of unconcentrated antibiotics of similar spectrum (cefotaxime)or oral antibiotics alone. Gianotti et alZ3studied various antibiotics in mice, in which acute pancreatitis was again induced by a diet deficient in choline and supplemented with ethionine. Some effect on survival rate was seen early but not later on after polymyxin B, amikacin, and amphotericin B were administered. All antibiotics used reduced the number of bacteria in the cecum, but only some reduced the rate of translocation of gram-positive and gram-negative microorganisms to all organs. The only controlled clinical study of selective decontamination was performed in a multicenter trial by Luiten et a135in 102 patients with severe acute pancreatitis. Patients were randomly assigned to a standard treatment group or a group given standard treatment plus selective decontamination, which consisted of oral administration of colistin sulfate, amphotericin B, and norfloxacin every 6 hours via application of a sticky paste containing 2% of these three drugs smeared along the gums every 6 hours. In addition, a rectal enema was given every day containing all three antibiotics in the same dosage as the oral administration. This regimen was supplemented by a short-time systemic prophylaxis of cefotaxime, which was given every 8 hours until gram-negative microorganisms were eliminated from the oral cavity and rectum. Mortality rate was 35% in the control group and 22% in the group given selective decontamination ( P = .048). This difference was mainly caused by reduction of late mortality (>2 weeks) because of significant reduction of gram-negative pancreatic infection ( P = .003). Furthermore, the average number of laparotomies per patient was reduced in the group with selective decontamination ( P = .05), and gram-negative pancreatic infection was reduced from 33% to 8% ( P = .003). Further studies are required before this therapy can be recommended. CONCLUSIONS
Earlier studies on preventing pancreatic infection by use of antibiotic prophylaxis came to naught because later studies showed that the antibiotics used were inappropriate.lb,20, 26 In the meantime, considerable interest has been concentrated on antibiotics in pancreatic fluid and tissue in humans. Some controlled clinical studies have demonstrated benefits 40, 48, 49 All these from antibiotic prophylaxis in severe acute pan~reatitis.'~, studies, although prospective, were small, and the data were not uniform. The choice of antibiotic and the duration of therapy still remain debatable issues.29Powell et a145 have stated that assuming 30% of patients with prognostically severe acute pancreatitis develop infected pancreatic necrosis, a total sample size of 322 is required to detect a 50% reduction in the rate of infection, assuming a two-tailed test with a significance level of 5% and a study power of 90%. Even larger studies are required to evaluate reduction in the mortality rate.45Most clinicians nowadays, however, would hesitate to involve patients with severe acute
ANTIBIOTIC PROPHYLAXIS IN THE TREATMENT OF ACUTE PANCIEATITIS
655
pancreatitis in studies with a ”no-antibiotic arm”45and for ethical reasons would test different antibiotics only against one other.6 Current recommendations are not uniform. The American Society of Gastroenterology practice guidelines merely state that it is ”reasonable to initiate” antibiotic therapy in severe acute pan~reatitis.~ The United Kingdom guidelines for the management of acute pancreatitisZ4simply state that the place of antibiotics in severe acute pancreatitis is unclear. Strongly suspected or confirmed local infective complications (infected necrosis, pancreatic abscess, and infected fluid collections) require appropriate antibiotics in addition to formal drainage by percutaneous or surgical means. Prophylactic antibiotics are recommended before invasive procedures, such as ERCP and surgery. Finally, British workers state that there is a place for prophylactic antibiotics early in an attack of acute pancreatitis predicted as severe. Cefuroxime is currently the antibiotic recommended, but treatment duration is unclear.24The Spanish Consensus Conference concluded that all patients with acute pancreatitis and proven pancreatic necrosis should be treated for 2 weeks immediately after pancreatic necrosis is diagnosed by CT with imipenem 500 mg every 8 hours. If the patient remains critically ill, the duration of treatment may be extended.36The German Society of Gastroenterology in its consensus conference has stated that there is an indication for antibiotic prophylaxis in acute necrotizing pancreatitis (intrapancreatic and extrapancreatic necrosis) and in those patients with a severe course of the disease (multiorgan failure, C-reactive protein 2120 mg/L, Ranson score 23, APACHE I1 score 2 8 ) (in preparation), and this is also the authors’ recommendation. The duration of antibiotic treatment in necrotizing acute pancreatitis or the duration of an antibiotic prophylaxis depends on the course of the disease; antibiotic prophylaxis or treatment, however, should be given for not less than 7 to 10 days. Recommended antibiotics (Table 6 ) may be divided into antibiotics of first choice and those that represent a possible alternative. First-choice antibiotics are carbapenems, which combine the effect of broad-spectrum penicillins and broad-spectrum third-generation cephalosporins. Imipenem is a standard carbapenem with a strong activity against almost all gram-positive and gram-negative microorganisms, including anaerobics. At present, imipenem is the antibiotic with the broadest spectrum and the highest activity against aerobics. Imipenem is also an alternative for antibiotic combinations that are used as initial treatment in severe bacterial infections or polyinfections. Other first-choice antibiotics are the quinolones (ciprofloxacin, ofloxacin) in combination with metronidazole. Quinolones are highly active against gram-negative microorganisms, including Pseudomonas and Salmonella species, and-with few exceptions-are also effective against gram-positive microorganisms. The effect against anaerobics is insufficient; therefore, quinolones should be combined with metronidazole. Metronidazole is active against anaerobics (Bacteroidesfiagilis, Clostridium and anaerobic cocci).
m
m
m
Ureidopenicillins Cephalosporins (third generation) Quinolones
First choice Carbapenems Quinolones (second generation) Possible alternatives Cephalosporins (third generation)
Group
200400 mg
Ofloxacin IV X
2 times/d
2 times/d
100-200 mg
Ciprofloxacin IV X
500 mg X 2-3 times/d 300-600 mg X 3-4 times/d 300-600 mg X 3-4 times/d 300-600mg X 3 4 times/d
Metronidazole IV Lincomycins IV (clindamycin) Lincomycins IV (clindamycin) Lincomycins IV (clindamycin)
2-3 times/d 2-3 times/d
Mezlocillin Ceftazidime IV
X
X
500 mg 500 mg
Metronidazole IV Metronidazole IV
2-3 times/d 2-3 times/d
1-2 g x 2-3 times/d (up 3 g x 4 times/d) 1-2 g x 2-3 times/d 2-5 g X 3-4 times/d 1-2 g X 2-3 times/d
X X
Cefotaxime IV Ceftazidime IV
500 mg 500 mg
Dosage
Metronidazole IV Metronidazole IV
Combined With
0.5-1 g X 3-4 times/d 100-200 mg x 2 times/d 200-400 mg x 2 times/d
Dosage
Imipenem-cilastatin IV Ciprofloxacin IV Ofloxacin IV
Substance
Table 6. RECOMMENDED ANTIBIOTIC PROPHYLAXIS IN THE TREATMENT OF ACUTE PANCREATITIS
ANTIBIOTIC PROPHYLAXIS IN THE TREATMENT OF ACUTE PANCREATITIS
657
Possible alternatives are third-generation cephalosporins, ureidopenicillins, such as piperacillin, both in combination with metronidazolole, and third-generation cephalosporins and quinolones, both in combination with lincomycins. Cefotaxime, a third-generation cephalosporin, is more active than the second-generation cephalosporins against gramnegative microorganisms but less active against some gram-positive microorganisms. Cefotaxime should therefore be given in cases of severe infection caused by gram-negative microorganisms and in combination with metronidazole against gram-positive microorganisms. Ceftazidime has a similar spectrum but is, in addition, highly effective against Pseudomonas species. When staphylococci or anaerobics are suspected, ceftazidime can be combined with lincomycins (clindamycin). The main indication of mezlocillin, a broad-spectrum ureidopenicillin, is severe infection by gram-negative microorganisms, usually coming from bile ducts or the urogenital tract. A combination with metronidazole may be helpful. Clindamycin is an important antibiotic against severe infections, including anaerobic microorganisms such as staphylococci. When combined with third-generation cephalosporins and quinolones, it is especially helpful against staphylococci and anaerobic microorganisms. An additional primary prophylaxis against fungi during an antibiotic treatment or a selective gut decontamination is not recommended at the present time.
References 1. Araida T, Frey CF, Ruebner B, et al: Therapeutic regimens in acute experimental pancreatitis in rats: Effects of a protease inhibitor, a P-agonist, and antibiotics. Pancreas 11:132, 1995 2. Banks PA: Acute pancreatitis: Medical and surgical management. Am J Gastroenterol 89:S78, 1994 3. Banks PA: Practice guidelines in acute pancreatitis. Am J Gastroenterol92:377, 1997 4. Banks PA, Gerzof SG, Langevin RE, et al: CT-guided aspiration of suspected pancreatic infection: Bacteriology and clinical outcome. Int J Pancreatol 18265, 1995 5. Barie P S A critical review of antibiotic prophylaxis in severe acute pancreatitis. Am J Surg 172(suppl6A):38S, 1996 6. Bassi C, Falconi M, Talamini G, et al: Results of a multicenter clinical trial of pefloxacin versus imipenem in severe pancreatitis [abstr]. Gastroenterology 114A1378, 1998 6a. Bassi C, Falconi M, Talamini G, et al: Controlled clinical trial of pefloxacin versus imipenem in severe acute pancreatitis. Gastroenterology 115:1513, 1998 7. Bassi C, Pederzoli P, Vesentini S, et al: Behavior of antibiotics during human necrotizing pancreatitis. Antimicrob Agents Chemother 38:830, 1994 8. Baudin F, Ozier Y Early antibiotic treatment in acute necrotising pancreatitis. Lancet 346:1374, 1995 9. Beger HG, Bittner R, Block S, et al: Bacterial contamination of pancreatic necrosis: A prospective clinical study. Gastroenterology 91:433, 1986 10. Benveniste GL, Morris RG: Penetration of cefotaxime into pancreatic juice. Lancet 1:588, 1985 11. Bittner R, Block S, Buchler M, et al: Pancreatic abscess and infected pancreatic necrosis: Different local septic complications in acute pancreatitis. Dig Dis Sci 321082, 1987 12. Bradley I11 EL: A clinically based classification system for acute pancreatitis. Summary
658
RATSCHKO et a1
of the International Symposium on Acute Pancreatitis, Atlanta, GA, September 11 through 13, 1992. Arch Surg 128:586, 1993 13. Bradley I11 EL: A fifteen year experience with open drainage for infected pancreatic necrosis. Surg Gynecol Obstet 177215, 1993 14. Brattstrom C, Malmborg A-S, TydCn G: Penetration of clindamycin, cefoxitin, and piperacillin into pancreatic juice in man. Surgery 103:563, 1988 15. Buchler M, Malfertheiner P, Friess H, et a1 Human pancreatic tissue concentration of bactericidal antibiotics. Gastroenterology 103:1902, 1692 16. Craig RM, Dordal E, Myles L The use of ampicillin in acute pancreatitis. AM Intem Med 83:831, 1975 17. Delcenserie R, Yzet T, Ducroix JP: Prophylactic antibiotics in treatment of severe acute alcoholic pancreatitis. Pancreas 13:198, 1996 18. Drewelow B, Koch K, Otto C, et al: Penetration of ceftazidime into human pancreas. Infection 21:229, 1993 19. Fedorak IJ, KO TC, Dpricin G, et a1 Secondary pancreatic infections: Are they distinct clinical entities? Surgery 112:824, 1992 20. Finch WT, Sawyers JL, Schenker S: A prospective study to determine the efficacy of antibiotics in acute pancreatitis. Ann Surg 183:667, 1976 21. Foitzik T, Fernhdez-del Castillo C, Ferraro MJ, et al: Pathogenesis and prevention of early pancreatic infection in experimental acute necrotizing pancreatitis. AM Surg 222:179, 1995 22. Gerzof SG, Banks PA, Robbins AH, et al: Early diagnosis of pancreatic infection by computed tomography-guided aspiration. Gastroenterology 93:1315, 1987 23. Gianotti L, Munda R, Gennari R, et al: Effect of different regimens of gut decontamination on bacterial translocation and mortality in experimental acute pancreatitis. Eur J Surg 161:85, 1995 24. Glazer G, Mann DV: United Kingdom guidelines for the management of acute pancreatitis. Gut 42(suppl 2):Sl-S13, 1998 25. Gregg JA, Maher L, DeGirolami PC, et al: Secretion of p-lactam antibiotics in pure human pancreatic juice. Am J Surg 150:333, 1985 26. Howes R, Zuidema GD, Cameron JL: Evaluation of prophylactic antibiotics in acute pancreatitis. J Surg Res 18:197, 197.5 27. Isaji S, Suzuki M, Frey CF, et al: Role of bacterial infection in diet-induced acute pancreatitis in mice. Int J Pancreatol 11:49, 1992 28. Isenmann R, Buchler MW Infection and acute pancreatitis. Br J Surg 81:1707, 1994 29. Johnson C D Antibiotic prophylaxis in severe acute pancreatitis. Br J Surg 83:883, 1996 30. Koch K, Drewelow B, Brinckmann W Die Pankreaspenetration von Ofloxacin-Eine Pilotstudie. Z Gastroenterol 31:587, 1993 31. Koch K, Drewelow 8, Liebe S, et al: Die Pankreasgangigkeit von Antibiotica. Chirurg 62:317, 1991 32. Lange JF, van Cool J, Tytgat GNJ: The protective effect of a reduction in intestinal flora on mortality of acute haemorrhagic pancreatitis in the rat. Hepatogastroenterology 3428, 1987 33. Lankisch PG, Banks PA: Pancreatitis. Berlin, Springer 1998 34. Lankisch PG, Klesel N, Seeger K, et al: Penetration of cefotaxime into the pancreas. Z Gastroenterol 21:601, 1983 35. Luiten EJT, Hop WCJ, Lange JF, et al: Controlled clinical trial of selective decontamination for the treatment of severe acute pancreatitis. Ann Surg 222:57,1995 36. Martinez JF, Palazon JM, Perez-Mateo M: Antibioterapia profillctica en pancreatitis aguda: Resultados de una conferencia de consenso. Rev Esp Enf Digest 89:781, 1997 37. McFadden DW, Reber HA: Indications for surgery in severe acute pancreatitis. Int J Pancreatol 15:83, 1994 38. Mithofer F, Femandez-del Castillo C, Ferraro MJ, et al: Antibiotic treatment improves survival in experimental acute necrotizing pancreatitis. Gastroenterology 110:232, 1996 39. Moody FG, Haley-Russell D, Muncy DM: Intestinal transit and bacterial translocation in obstructive pancreatitis. Dig Dis Sci 40:1798,1995 40. Pederzoli P, Bassi C, Vesentini S, et al: A randomized multicenter clinical trial of
ANTIBIOTIC PROPHYLAXISIN THE TREATMENT OF ACUTE PANCREATITIS
659
antibiotic prophylaxis of septic complications in acute necrotizing pancreatitis with imipenem. Surg Gynecol Obstet 176:480, 1993 41. Pederzoli P, Falconi M, Bassi C, et al: Ofloxacin penetration into bile and pancreatic juice. J Antimicrob Chemother 23:805, 1989 42. Pederzoli P, Falconi M, Bassi C, et a1 Ciprofloxacin penetration in pancreatic juice. Chemotherapy 33397,1987 43. Pederzoli P, Orcalli F, Falconi M, et al: Penetration of mezlocillin into pancreatic juice. J Antimicrob Chemother 17397, 1986 44. Persky L, Schweinburg FB, Jacob S, et al: Aureomycin in experimental acute pancreatitis of dogs. Surgery 30:652,1951 45. Powell JJ, Miles R, Sirivardena AK Antibiotic prophylaxis in the initial management of severe acute pancreatitis. Br J Surg 85:582, 1998 46. Roberts EA, Williams RJ: Ampicillin concentrations in pancreatic fluid bile obtained at endoscopic retrograde chohgiopancreatography (ERCP). Scand J Gastroenterol 14:669. 1979 47. Runkel NSF, Moody FG, Smith GS, et al: The role of the gut in the development of sepsis in acute pancreatitis. J Surg Res 51:18, 1991 48. Sainio V, Kemppainen E, Puolakkainen P, et al: Early antibiotic treatment in acute necrotising pancreatitis. Lancet 346:663, 1995 49. Schwarz M, Isenmann R, Meyer H, et al: Antibiotika bei nekrotisierender Pankreatitis: Ergebnisse einer kontrollierten Studie. Dtsch Med Wochenschr 122:356, 1997 50. Tenner S, Sica G, Hughes M, et al: Relationship of necrosis to organ failure in severe acute pancreatitis. Gastroenterology 113:899, 1997 51. Trudel JL, Wittnich C, Brown RA: Antibiotics bioavailability in acute experimental pancreatitis. J Am Coll Surg 178475, 1994 52. Widdison AL, Karanjia ND, Reber HA: Antimicrobial treatment of pancreatic infection in cats. Br J Surg 81:886, 1994
Address reprint requests to Paul Georg Lankisch, MD Medizinische Klinik Stadtisches Klinikum Boegelstrasse 1 D-21339 Liineburg Germany