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Bacterial Infections and Their Emerging Resistant Patterns in HCV Patients Following Liver Transplantation in Egypt Protocol of Thesis Submitted for Partial Fulfillment of the Degree of M.D. in Tropical Medicine By Yasmine Mahmoud Massoud M.B.B.Ch., M.Sc. (Tropical Medicine, Ain Shams University) Under Supervision of Professor Doctor/ Mohammed Fawzy Montasser Ex-Dean Faculty of Medicine Professor of Tropical Medicine Faculty of Medicine - Ain Shams University Professor Doctor/ Mahmoud Shawky Al-Metieny Professor Of General Surgery Director Of Ain Shams Center For Organs Transplantation (Ascot) Faculty of Medicine - Ain Shams University Doctor/ Nadia Abdel Aaty Abdel Kader Lecturer of Tropical Medicine Faculty of Medicine - Ain Shams University Doctor/ Sara Mahmoud Abd El-Hakam Lecturer of Tropical Medicine Faculty of Medicine - Ain Shams University Doctor/ Hany Mansour Khalil Dabbous Lecturer of Tropical Medicine Faculty of Medicine - Ain Shams University Faculty of Medicine Ain Shams University 2010 Introduction Liver transplantation is considered the treatment of choice for patients with end stage liver disease who have failed standard therapy. The development of liver transplantation has revolutionized the field of hepatology and greatly improved the outlook of patients suffering from various liver diseases. This procedure is now applied worldwide as treatment for a large number of irreversible acute and chronic liver diseases for which there were previously no other treatment options (Zhu et al., 2009). The primary goals of liver transplantation are to prolong life and to improve the quality of life. Thus, it is essential to optimize patient selection and ideally time the transplant procedure so as to gain the maximum benefit (Kanwal et al., 2005). Current problems encountered following OLT are surgical and Non- surgical complications which are mostly pulmonary. Infection is the main cause of death following OLT. Early infections, mostly intra-abdominal and pulmonary, are bacterial or fungal (Moncorgé et al., 1989).Biliary strictures and incisional hernias are the most common surgical complications encountered late after liver transplantation (Porrett et al., 2009). More than two-thirds of liver transplant recipients have infection in the first year after transplantation, and infection is the leading cause of death in these patients. In addition, release of cytokines during the infection may have other indirect and negative effects, including allograft injury, opportunistic super infection, and malignancy (Rubin, 2002). There are many factors associated with an increased risk of infection, such as disruption of the normal bacterial flora resulting from the extensive use of broad-spectrum antimicrobial agents, prolonged or intensive antibacterial chemo therapy, severe and chronic underlying diseases (uremia, liver cirrhosis), nutritional status, surgical and/or invasive procedures, the hospital environment, immunosuppressive therapy, and other factors causing immunological deficiency (e.g. viral and fungal co-infections) (Kawecki et al., 2009) The most frequent infections are surgical site (16%) and urinary tract (11%). Etiologies included bacterial (48%) and fungal (22%) causes. The most common pathogens are Escherichia coli (20%), among which, 40% were extended-spectrum beta-lactamase ESBL-producers, and Enterococcus spp. (11%). More than half of the infectious episodes (58%) occurred in the first 4 months after transplantation (Garcia et al., 2009). Patients may become infected with nosocomial, antimicrobial-resistant bacteria, including methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus faecalis, Clostridium difficile, and antimicrobial-resistant gram-negative bacteria (Del Pozo, 2008). Methicillin-resistant Staphylococcus aureus (MRSA) infection frequently complicates the postoperative course in diseased-donor liver transplantation. The incidence and risk factors of MRSA infection after Living-donor Liver transplantation (LDLT), however, are unclear (Hashimoto et al., 2008).The most common sites of MRSA infection are blood (42%), lung (38%), and abdomen (29%) (Schneider et al., 2005). Aim of the Work To study the incidence, types, risk factors and causative organisms of bacterial infections in HCV patients following Liver Transplantation and identify the emerging resistant strains and their proper antimicrobial therapy. Patients and Methods Study design: Prospective Descriptive Follow up study. Participants: At least 30 Patients with eligible criteria for liver transplantation in Ain Shams Specialized, Wadi El Nile and Egypt Air Hospitals will be recruited and followed up during a period of 3months following transplantation. Patients will be divided into 2 groups: Group 1 includes patients who had a postoperative course free from infections. Group 2 includes patients who had postoperative bacterial infections whom will be further analyzed into a subgroup without emerging strains or antibiotic resistance and another subgroup who experienced bacterial infection with emerging or resistant strains. Inclusion criteria: - Patients with end stage liver disease who are hepatitis C virus positive and who are candidates for liver transplantation. - Age between 18-60 Years, including males and females. - Accepting participation in the current study and signing a written consent form. Exclusion criteria: - Patients with other etiologies for end stage liver disease (HBV, PBC,…) - Intra operative or early postoperative death. • Special Follow-up items for the Current Study: 1. All patients will be checked for the possible risk factors suggestive of acquiring infection. Preoperatively: Demographic data as (donor age & sex, recipient age & sex). Child & MELD scores Leucopenia and thrombocytopenia Co-morbidities including (Diabetes, Hypertension,...) Nutritional status (adequately, moderately, poorly nourished) (Morgan et al ., 2006). Serum sodium Documented or suspected SBP and 3rd generation cephalosporin administration. GRWR (Graft Receipient Weight Ratio). Degree of steatosis of the graft (<15%) Renal impairment. Intraoperatively: Total operative period Cold Ischemia Time. Warm Ischemia Time. Amount of transfusion of blood or blood products. Type of biliary anastomosis. Postoperatively: ICU stay (average 3-5 days) Duration of central venous line and catheter insertion. Duration of abdominal drain Duration of hospital stay Immunosuppression given as regards: type, number & dosage of drugs. 2. Patients will be identified and classified into the 2 groups based on; a) clinical assessment b) laboratory results with stress on ; CBC with differential count, CRP, serum ferritin, liver profile abnormalities c) pancultures; urine, sputum, blood, ascitic, bile, stool and abdominal drain cultures. 3. Infections will be defined using criteria proposed by the Center for Disease Control and as reported in liver transplant recipients (Garner et al., 1988). *In patients with skin infections: A sample of the discharge will be taken from the infected tissue by using a sterile dry cotton wool swab. And will be examined by: - Microscopic examination: by Gram smear for pus cells and bacteria. - Culture will be done on blood agar and MacConkey’s agar (Colle et al., 1996). Diagnosis of wound infection is based upon the presence of redness/induration and the presence of pus on exploration and/or positive wound culture. * In patients with clinical picture suggestive of urinary tract infection: Mid-stream urine samples will be collected in a sterile dry container (about 20 cc of urine). - In patients with indwelling urinary catheters, urine samples will be collected by aspiration of urine from the distal end of the catheter by a sterile syringe after clamping the drainage tube above the catheter-tube junction. Samples will be examined by: - Microscopic examination: to detect the presence of the increased numbers of polymorphs (pyuria). - Estimation of viable bacterial colony count in uncentrifuged urine sample: In mid-stream urine, more than 105 CFU/ml indicates urinary tract infection. Less than 105 without pus cells or patient's complain indicate urethral contamination. - Culture: will be inoculated on blood agar and Mac Conkey’s agar. For diagnosis of urinary tract infection 1 of the following criteria should be present: Patient has at least 1 of the following signs or symptoms with no other recognized cause: fever (38C), urgency, frequency, dysuria, or suprapubic tenderness and patient has a positive urine culture, that 5 is, ≥10 microorganisms per cc of urine with no more than 2 species of microorganisms. * In patients with clinical picture suggestive of pneumonia Sputum samples will be taken from suspected patients. Sputum samples will be collected in the morning before any mouth wash by coughing deeply in a sterile dry container. In comatosed patients, samples will be taken by naso-tracheal suction. The samples will be checked for: - Physical examination: colour, aspect and odour. - Microscopic examination by: Wet preparation: to detect epithelial cells and pus cells, Gram smear: for pus cells and to identify gram-positive or gram-negative organisms. - Culture: will be done on blood agar, MacConkey’s agar and chocolate agar and incubated at 37°C, both aerobically and anaerobically, then examined after 24 hours (Colle et al., 1996). Diagnosis of pneumonia is based on pulmonary infiltrates together with clinical symptoms suggestive of lower respiratory tract infection, the identification of a relevant etiologic microbial agent, and the absence of an alternative diagnosis during follow-up. Additional confirmative criteria are the response to adequate antimicrobial treatment or results of necropsies demonstrating the presence of pneumonia. * Blood cultures: (will be done for all patients with manifestations of infections). They will be collected before the start of any antimicrobial treatment. - Blood samples will be taken under complete aseptic condition. - Withdrawing 10-12 ml of blood by a sterile syringe. - Inserting the needle through the rubber line of the bottle cap and dispensing blood into each culture bottle. - Wiping the top of each culture bottle by an ethanol-ether swab and replacing the protective caps, then gently mixing the blood with the broth. - Then incubating the inoculated media (Reimer et al., 1997). Diagnosis of Blood stream infection (BSI) is defined as the isolation of gram-positive cocci, gram-negative rods, or any kind of fungi in the blood culture. - Antibiotic susceptibility test will be done. - Cultures will be repeated after 10 days from the start of antibiotic treatment. - Infection resolution will be identified when clinical manifestations of infection improve and cultures become negative. *Ascitic fluid culture (will be done for all patients with manifestations of bacterial peritonitis or suspected to be so) Samples will be collected before the start of any antimicrobial treatment. - Samples will be taken under complete aseptic conditions. - Withdrawing 2 ascitic samples, each 20 ml by a sterile syringe. - Chemical and bacteriological testing will be done. *Bile samples for those suspected to have biliary tract infection. In cases of suspected sepsis induced cholestasis (SIC), Cultures from blood, biliary tube, abdominal drains , urine, and sputum will be done and culture based treatment will be started accordingly. • Duration of the study: Will be 1 year. Data Management and Statistical Analysis: To assess risk factor status, two groups of patients will be considered. Group I: Patients who did not develop infection at 3 months. Group II: Patients who aquired infection during the ﬁrst 3 months post-transplant. All the pre-operative variables and post-operative events will be compared between the two groups using univariate and multivariate analysis. Student’s t-test or the Mann–Whitney U-test will be used for quantitative data and Pearson’s chi-square or Fisher’s exact test for categorical data. Differences will be considered statistically signiﬁcant when the p value is <0.05. Data will be shown as mean ± SD or as median and range or as percentages. All variables signiﬁcant in univariate analysis will be analysed by a multiple regression logistic model. The forward stepwise logistic strategy will be applied, and variables will be included in the model if the log likelihood ratio chi-square test is signiﬁcant. REFERENCES Colle, J.G.; Duguid, J.P.; Fraser, A.G.; et al. (1996): Practical Medical Microbiology, 14th edition. Edited by Mackie and McCartney. Churchill, Livingstone. Del Pozo, J. (2008): Update and actual trends on bacterial infections following liver transplantation. World J Gastroenterol ; 14(32): 4977– 4983. García-Prado E, Cordero E, Alamo JM et al. (2009): Descriptive study of infectious complications in 109 consecutive liver transplant recipients Enferm Infecc Microbiol Clin. Apr;27(4):199-205. Garner JS, Jarvis WR, Emori TG, et al.(1988): CDC definitions for nosocomial infections, 1988. Am J Infect Control ; 16: 128. Hashimoto M, Sugawara Y, Tamura S et al. (2008): Methicillin- resistant Staphylococcus aureus infection after living-donor liver transplantation in adults. Transpl Infect Dis. ;10(2):110-6. Kanwal, F.; Dulai, G.S.; Spiegel, B.M.; et al. (2005): A comparison of liver transplantation outcomes in the pre- vs. post-MELD eras. Aliment. Pharmacol. Ther., 21(2):169-177. Kawecki D, Chmura A, Pacholczyk M et al. (2009): Bacterial infections in the early period after liver transplantation: Etiological agents and their susceptibility. Med Sci Monit;15(12): CR628-637. Moncorgé C, Baudin F, Vigouroux C, et al. (1989): Liver transplantation in adults: postoperative management and development during the first months. Ann Fr Anesth Reanim. ;8(5):497-517. Morgan M, Madden A, Soulsby C et al. (2006): Derivation and validation of a new global method for assessing nutritional status in patients with cirrhosis.Hepatology ; 44:823-835. Porrett PM, Hsu J and Shaked A. (2009): Late surgical complications following liver transplantation. ;15 Suppl 2:S12-8. Reimer, L.G.; Wilson, M.L. and Weinstein, M.P. (1997): Update on detection of bacteraemia and fungaemia. Clin. Microbiol; Rev., 10 (3): 444-465. Rubin RH (2002): The direct and indirect effects of infection in liver transplantation: Pathogenesis, impact, and clinical management. Curr Clin Top Infect Dis; 22:125-154. Schneider C.R, Buell J.F, M. Gearhart M et al. (2005): Methicillin- Resistant Infection in Liver Transplantation: A Matched Controlled study. Transplantation Proceedings, 37(2):1243-1244. Zhu, J.Y.; Gao, P.J.; Li, G.M.; et al. (2009): Analysis of 565 cases of liver transplantation at a single transplantation center. Beijing Da Xue Xue Bao, 41(3): 368-372.
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