2Antimicrobial Therapy TOKYO GUIDELINESTokyo International Consensus MeetingApril 1-2, 2006@ Keio Plaza Hotel, Tokyo, JapanJapan, Singapore, Korea, HongKong, China, Taiwan, Argentina, Germany, South Africa, Italy, France, USA, Indonesia, Australia, Thailand, Malaysia, New Zealand, Philippines (S.C. Hilvano: Department of Surgery, College of Medical & Philippine General Hospital)
3Antimicrobial Therapy INDICATIONAntimicrobial agents should be administered to all patients diagnosed as having acute cholangitis (recommendation A); the Antimicrobial agents should be administered as soon as the diagnosis of acute cholangitis is suspected or established.
4Antimicrobial Therapy Most important FACTORS FOR CONSIDERATION:Antimicrobial activity against causative bacteriaSeverity of cholangitisPresence/absence of renal and hepatic diseasePast history of antimicrobial administration to the patientLocal susceptibility patterns (antibiogram) of the suspected causative organismsBiliary penetration of the antimicrobial agents.The dose of the antimicrobial agent should be reducedfor patients with reduced renal function. Because mostcephalosporin, penicillin, aminoglycoside, and carbap-enem antimicrobial drugs are excreted by the kidneys,the dose is reduced for patients with nephropathy anddecreased renal function. The Sanford guide to antimi-crobial therapy, and Goodman and Gilman’s thepharmacological basis of therapeutics 19 recommend thatrenal function be estimated by the following formula:Creatinine clearance predicted from serum creatinine(×0.85 for females) = (140 − age)(optimum bodyweight (kg)) / (72 × serum creatinine mg/dl)62 where male optimum body weight is 50.0 kg kg/cm (150 cm and taller) and female optimum body weightis 45.5 kg kg/cm (150 cm and taller).
5Antimicrobial Therapy SELECTIONAntimicrobial drugs should be selected according to the severity assessment (recommendation A).Empirically administered antimicrobial agents should be changed for more appropriate agents according to the identiﬁed causative microorganisms and their sensitivity to antimicrobials (recommendation A).
7Antimicrobial Therapy DOSAGEAccording to local rules and regulationsDrug dosage adjustment should be done in patients with decreased renal function. The Sanford guide to antimicrobial therapy and Goodman and Gilman’s the pharmacological basis of therapeutics should be consulted (recommendation A).Drug dosage adjustment for ceftriaxone is not necessaryin patients with renal failure. But dose adjustment ofceftriaxone is indicated for patients with severe hepaticimpairment. 18 In addition, when biliary obstruction thatblocks the enterohepatic circulation of bile is present,the administration of third- and fourth-generation ceph-alosporins may replace the intestinal ﬂ ora and disturbvitamin K absorption, in turn risking coagulopathichemorrhage. This phenomenon, leading to bleedingtendency, can be enhanced in patients with comorbidliver diseases or liver failure due to severe acute chol-angitis. Intravenous administration of vitamin K may beindicated in these situations.
8Antimicrobial Therapy DURATIONFor patients with moderate (grade II) or severe (grade III) acute cholangitis, antimicrobial agents should be administered for a minimum duration of 5–7 days. More prolonged therapy could be required, depending on the presence of bacteremia and the patient’s clinical response, judged by fever, white blood cell count, and C-reactive protein, when available (recommendation A).For patients with mild (grade I) acute cholangitis, the duration of antimicrobial therapy could be shorter (2 or 3 days) (recommendation A).An important and fruitful discussion was held regardingthe duration of antimicrobial therapy for patientswith acute cholangitis (see “Discussion”). In summary,patients with moderate (grade II) or severe (grade III)acute cholangitis should receive a minimum durationof therapy of 5–7 days, and then, based on the anatomyof the disease and the presence of bacteremia, andtheir clinical responses, patients may need more pro-longed therapy. However, for the large group of pa-tients with mild (grade I) cholangitis, 2 or 3 days ofantimicrobial therapy is likely to be sufﬁ cient. Need-lessly prolonged antimicrobial therapy risks adversereactions to the antimicrobials, and intensiﬁ es pressurefor the development and acquisition of resistantbacteria.
9Antimicrobial Therapy BILIARY PENETRATIONBiliary penetration should be considered in the selection of antimicrobial agents in acute cholangitis (recommendation A).It has been debated whether antimicrobials with goodbiliary penetration should be recommended for acutecholangitis. Indeed, there was a common belief, particu-larly in Japan, that antimicrobial agents with excellentbiliary penetration are more effective for the treatmentof acute cholangitis. However, there are no clinical orexperimental data to strongly support the recommenda-tion of antimicrobials with excellent biliary penetrationfor these patients. In fact, in most patients with acutecholangitis, biliary obstruction is usually present, andantimicrobial drugs may not be detected in bile even ifthey demonstrate excellent biliary excretion in normalconditions (level 3b–4). 20–27Nevertheless, at the Consensus Meeting, we reacheda consensus that the importance of biliary penetrationshould be emphasized for the empirical selection ofantimicrobial agents (Fig. 3). For details, see “Discussionat the Tokyo International Consensus Meeting.” InTable 3, we list antimicrobial agents with good biliarypenetration.
10Principles of Management Septic ShockAscending CholangitisClose monitoring (vital signs, I/O)Hemodynamic support with IV fluids and vasopressorsIdentify underlying cause for sepsisABC assessmentIV Fluid resuscitation with crystalloids (e.g. plain NSS)Parenteral antibioticsBiliary decompression (severe cases)Extracorporeal shockwave lithotripsy (ESWL) for choleliths
13PROGNOSISmore serious than cholecystitis, potentially life-threateningprognosis depends on cause (best to worst) - stones, benign strictures, sclerosing cholangitis, cancer
14Looking Ahead – Ascending Cholangitis PrognosisComplicationsDepends on the following:Early recognition and treatment of cholangitisResponse to therapyUnderlying medical conditions of the patientMortality rate: 5-10%, (higher in patients who require emergency decompression or surgery)Good response to antibiotics = good prognosisLiver failure, hepatic abscess, microabscessAcute renal failureBacteremia, sepsis (gram-negative)
15Looking Ahead – Septic Shock PrognosisComplicationsDepends on the following:Severity of illnessCo-morbiditiesAgeResponse to antibioticsAcute respiratory distress syndrome (ARDS)Renal dysfunctionDisseminated intravascular coagulation (DIC)Mesenteric ischemiaMyocardial ischemia and dysfunction
17MANAGEMENT Medications: antibiotics active against enteric organisms treatment guidelines from The Medical Letter for intra-abdominal infections reasonable first choicespiperacillin-tazobactam (Zosyn)ticarcillin-clavulanate (Timentin)ampicillin-sulbactam (Unasyn)carbapenem - ertapenem, imipenem/cilastatin, or meropenemReference - Clin Infect Dis 2003 Oct 15;37(8):997previous options no longer recommended cefoxitin (Mefoxin) no longer reliable for Bacillus fragiliscefotetan (Cefotan) withdrawn from marketsome clinicians prefer piperacillin-tazobactam or ampicillin-sulfactam, with or without aminoglycoside, for bacteremia from biliary tractoptions if allergic to beta-lactamsfluoroquinolone (ciprofloxacin, levofloxacin or moxifloxacin) plus metronidazoletigecyclinein severely ill patientscover Pseudomonas with piperacillin-tazobactam, imipenem, meropenem, ceftazidime, cefepime, aztreonam or ciprofloxacinadd metronidazole for B. fragilis coverageaminoglycoside can be addedReference - Treat Guidel Med Lett 2007 May;5(57):33 TOC
18tigecycline (Tygacil) tigecycline (Tygacil) FDA approved for IV treatment of complicated intra-abdominal infections and complicated skin and skin structure infections in adultsbroad spectrum of activity including methicillin-resistant Staphylococcus aureus (MRSA)may be used as empiric monotherapy for complicated appendicitis, infected burns, intra-abdominal abscesses, deep soft tissue infections, and infected ulcersReference - Infection Control Today 2005 Jun 16tigecycline not very effective against Pseudomonas (Prescriber's Letter 2005 Jul;12(7):38)tigecycline should be used judiciously to reduce resistance, could be useful for resistant organisms but not Pseudomonas (The Medical Letter 2005 Sep 12;47(1217):73)
19COMPLICATIONS Complications: bacterial cholangitis led to sclerosing cholangitis in case report (BMC Gastroenterology 2002 Jun 3;2:14)Associated conditions:bile stasisrenal dysfunction and failure common with toxic cholangitis(1)
21SOURCES20072007Antimicrobial therapy for acute cholangitis: Tokyo GuidelinesAtsushi Tanaka, Tadahiro Takada, Yoshifumi Kawarada, Yuji Nimura, Masahiro Yoshida, Fumihiko Miura, Masahiko Hirota, Keita Wada, Toshihiko Mayumi and Harumi Gomi, et al.Journal of Hepato-Biliary-Pancreatic SurgeryVolume 14, Number 1, 59-67Flowcharts for the diagnosis and treatment of acute cholangitis and cholecystitis: Tokyo GuidelinesFumihiko Miura, Tadahiro Takada, Yoshifumi Kawarada, Yuji Nimura, Keita Wada, Masahiko Hirota, Masato Nagino, Toshio Tsuyuguchi, Toshihiko Mayumi and Masahiro Yoshida, et al.Journal of Hepato-Biliary-Pancreatic SurgeryVolume 14, Number 1, 27-34
222008 2007 http://www.springerlink.com/content/a8v37tr741175070/ Review PaperMicrobiology and Management of Abdominal InfectionsItzhak BrookDigestive Diseases and SciencesVolume 53, Number 10,Diagnostic criteria and severity assessment of acute cholangitis: Tokyo GuidelinesKeita Wada, Tadahiro Takada, Yoshifumi Kawarada, Yuji Nimura, Fumihiko Miura, Masahiro Yoshida, Toshihiko Mayumi, Steven Strasberg, Henry A. Pitt and Thomas R. Gadacz, et al.Journal of Hepato-Biliary-Pancreatic SurgeryVolume 14, Number 1, 52-58