ročník 11,2003 č.4
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Antibiotic Therapy in Biliary Tract Surgery

Oliverius M.

Department of Surgery
Na Homolce Hospital, Prague, Czech Republic

The diseases of the gallbladder and the biliary tree belong to common disorders. Apart from surgical therapy, most of these conditions require also the treatment with antibiotics. Their use is often based on empirical experience and presumed identity of the causative microbial agent. I would like to present an overview of my own experience and pertinent literary data and propose a rational therapeutic procedure.
Infections of the gallbladder and the biliary tree present a problem of everyday medical practice. In spite of the significant progress in the surgical and non-surgical intervention therapy of this group of diseases the infections of the biliary tract have still major share in the morbidity and mortality of patients. Early start of an appropriate antibiotic therapy often significantly influences further course of the disease and its possible complications and long-term consequences.
The prophylactic administration of antibiotics in the elective bile tract surgery is of importance as well. Different schemes and regimes are used for the antibiotic therapy and prophylaxis.
Apart from general guidelines, it is important to take into account many other factors such as the causative agent of the infection (community acquired or nosocomial infections - patients treated with antibiotics repeatedly or for a long time immediately before the surgery with modified microbial flora), type of patient especially with regard to severe concurrent diseases and ensuing pathophysiological changes of their organism, pharmacokinetics of antibiotics and last but not least economic burden of the chosen therapy.
Concerning the antimicrobial therapy of biliary tract infections, we usually start the therapy based on the empirical knowledge of the most common causative agents and their respective sensitivity to antibiotics. The most common agents involved in biliary tract infections are enterobacteria (Escherichia coli, Klebsiella spp., Proteus mirabilis), Gram-positive cocci - enterococci and anaerobes (Bacteroides fragilis, anaerobic cocci and Clostridium spp.). Another causative agent present especially in cases of acute cholangoitis and playing an important role in its pathogenesis is Pseudomonas aeruginosa. Infection by Candida spp can be involved in immunosuppressed patients or patients previously treated with.
Based on this information, it is possible to propose general properties of an appropriate antibiotic. An optimal drug should penetrate easily into the bile and its excretion and efficacy is not affected by cholestasis, which often causes or accompanies biliary tract infections. Such a drug should exert maximum effect on the presumed microbial flora in the respective region.
Based on extensive studies conducted, several groups of antimicrobial agents were chosen for the empirical therapy of biliary tract infections: broad-spectrum penicillins in combination with aminoglycosides and quinolones, or metronidazole. Cephalosporins of the second and third generations have appeared already for a long time as optimal due to their excellent penetration into the bile.

Prophylactic use of antibiotics

During the years, many often disputable schemes and recommendations were proposed concerning the prophylactic use of antibiotics in elective surgery and intervention therapy of the biliary tract based on numerous studies.
The prophylactic use of antibiotics prior ERCP and other interventions is still under debate. If we consult the recommendations of the British Society for Gastroenterology from 1996, the antibiotic prophylaxis prior ERCP is indicated only in patients with high risk of endocarditis or symptomatic bacteriemia due to immune suppression or neutropenia. The most often recommended drugs are aminopenicillins in combination with gentamycin. Metronidazole is often added in patients with neutropenia. In case of an allergic patient, vancomycin or teicoplanin can be used. Prophylactic administration of antibiotics is also recommended in all patients with cholestasis or pancreatic pseudocyst. In this case oral ciprofloxacin or parenteral gentamycin is being recommended (parenteral quinolones, cephalosporins or ureidopenicillins are also suitable).
In case of elective surgery in non-compromised individuals, prophylactic administration of antibiotics prior the most common surgical procedure - cholecystectomy - is not indicated. Only one study recommends oral cephalosporin (ceftibuten) for better wound healing, but there exist a general agreement that prophylactic administration of antibiotics before cholecystectomy is not indicated.
In case of bile duct surgery and surgery including liver resection the prophylactic use of antibiotics is appropriate. Based on the specific antimicrobial situation and individual experience, it is adequate to use aminopenicillins potentiated with beta-lactamase inhibitors possibly in combination with metronidazole or second and third generation cephalosporins, which, however, do not cover enterococci and anaerobes. It is usually enough to administer one adequately large dose together with premedication or possibly another two doses in a given time scheme.

Acute cholecystitis

A total of 90-95% cases of acute gallbladder inflammations are connected with bile stones. A gallbladder distension with edema is the pathogenetic factor involved. The inflammation may progress into tissue necrosis due to combined pathogenetic action of bile acids, phospholipase A, lysolecithin, prostaglandins and microbial agents. Microorganisms are present in over 75% of cases with E.coli, Klebsiella spp. and enterococci as predominant species.
In 5-10% of all acute cholecystitis cases no bile stones were present. Even in these cases, mucosal exposition to the stagnating bile and ischemia play important role, especially in patients at ICUs after serious surgery or trauma. Releasing the obstruction is a decisive therapeutic moment. In today's era of laparoscopic cholecystectomy surgeries the number of conservatively managed acute cholecystitis cases dropped significantly and the current causal therapy is laparoscopic (converted, if necessary) cholecystectomy within the first 48-72 hours from the onset of symptoms. Should this interval be prolonged or in patients who would not tolerate surgery due to co-morbidity and in cases where conservative therapy does not relieve the symptoms, it is possible to perform percutaneous drainage and decompression of gallbladder under sonographic or CT control followed by postponed cholecystectomy when the status of the patient is stabilized. A long-term antimicrobial therapy targeted onto detected agent is indicated exactly in these cases.
Potentiated aminopenicillins belong among drugs of first choice, possibly combined with metronidazole, alternatively second and third generation cephalosporins or antibiotics from other groups (broad spectrum penicillins, fluoroquinolones).

Acute cholangoitis

Acute cholangoitis is the combination of biliary obstruction with increasing pressure in the biliary tree and presence of microbial agent. This severe condition may lead to septic shock and death without immediate and aggressive therapy.
Again, the etiology is dominated by occurrence of bile stones, however recently, due to expanding biliary tract surgery for benign and malignant diseases, the post-surgical stenoses of biliary tree play an important role as well, caused by iatrogenic damage to the biliary tree or post-surgical stenoses of the biliodigestive anastomoses. The therapy is predominantly causal with urgent or elective decompression of the biliary tract by endoscopy or via transhepatic route.
The antimicrobial therapy plays an important role here and it should meet following requirements: bactericidal effect, sufficiently aggressive nature both in dose as well as intervals of administration, effective against anticipated microbial agents, sufficient penetration into bile (as the obstruction exists here). At such severe condition the third generation cephalosporins belong among drugs of choice, especially cefoperazon with its excellent penetration into even obstructed bile and with relatively low frequency of adverse effects. In order to eliminate bacteriemia it is possible to combine cefoperazon with sufficient dose of aminoglycosides during the first three days of treatment. Other possibilities include combinations of potentiated aminopenicillins with aminoglycosides and metronidazole, carbapenems or ureidopenicillins.
It is important, in this context, to mention the problem of persistent biliary tree stenosis, especially after operations near to the hepatic junction. The patients often suffer from repeated attacks of cholangoitis, sometimes resulting in development of liver abscesses. In a Dutch study, the long-term antimicrobial therapy (lasting for the average of 3.4 months) had been used, composed of trimethoprim-sulphametoxaozole or ciprofloxacin (in one patient aminopenicillin with beta-lactamase inhibitor was used). This long-term therapy led to a significant reduction or even vanishing of repeated biliary tract infections. The study involved 54 patients with the history of repeated post-surgical cholangoitis after surgery for malignant diseases of the gallbladder and bile ducts.
As far as the length of antibiotic therapy is concerned, can be stated in general that the treatment should last until the biliary tract obstruction has resolved and the clinical symptoms recede. If the obstruction persists or we are dealing with severe attack of cholangoitis, the therapy should be prolonged for up to several weeks.

Biliary peritonitis and biliary leaks

The therapy of complications like these is based upon their etiology. The development of biliary surgery including laparoscopic techniques undoubtedly led to increase of biliary leaks and cases of biliary peritonitis. In such cases, the bile is sterile and if the indication for surgical revision is done in time, it is not necessary to use antibiotics. It is possible to think about indicating a prophylactic administration of antibiotics at interventions that include insertion of stents for biliary leaks, but even here this is not a prerequisite.
There is no doubt that in the case of biliary peritonitis after gallbladder perforation during acute inflammation the use of antibiotics is necessary.

Conclusion

It is certainly impossible to propose a general guideline for the use of antibiotics in the surgical therapy of gallbladder and biliary tract. Considering the complexity of the respective matter and the number of factors that play role here, it is possible to conclude with a summary of pertinent general rules: consideration of expected microbial agents present in the biliary tract and timely detection thereof; surgical or non-surgical invasive decompression of the biliary tree; the use of antibiotic with a proper antimicrobial spectrum; high-rate penetration into the bile and low adverse effects.
CEFOPERAZON (CEFOBID), cephalosporin of a third generation that easily penetrates the bile even in presence of obstruction and with its bile concentration exceeding the MIC for most of causative agents, is one of highly effective antimicrobial agents in the field. CEFOPERAZON is not effective against enterococci and Bacteroides fragilis. A whole of 75% of the drug is excreted into the bile and only 25% is excreted via kidneys, making the dosage adjustment necessary only in patients with severe hepatorenal failure. The currently running multicentric trial evaluating the use of cefoperazon in the therapy of biliary infections will undoubtedly bring some more interesting findings.

Address for correspondence:

MUDr. M. Olivierus
Department of surgery
Na Homolce Hospital
Prague
Czech republic