Combined lung-liver-pancreas transplantation in a recipient with cystic fibrosis.

Cystic fibrosis (CF) affects multiple organs including the lung, liver, and pancreas. Lung transplant, liver transplant, and combined lung-liver transplant have become well-established therapies for CF patients with end-stage organ failure. Thus far, however, there has been limited experience with pancreas transplantation in CF. In this report, we detail the clinical history, transplant procedure, and post-operative recovery of a patient who underwent combined lung-liver-pancreas transplant for advanced CF.

Ex Vivo Perfusion Treatment of Infection in Human Donor Lungs.

Ex vivo lung perfusion (EVLP) is a platform to treat infected donor lungs with antibiotic therapy before lung transplantation. Human donor lungs that were rejected for transplantation because of clinical concern regarding infection were randomly assigned to two groups. In the antibiotic group (n = 8), lungs underwent EVLP for 12 h with high-dose antibiotics (ciprofloxacin 400 mg or azithromycin 500 mg, vancomycin 15 mg/kg, and meropenem 2 g). In the control group (n = 7), lungs underwent EVLP for 12 h without antibiotics. A quantitative decrease in bacterial counts in bronchoalveolar lavage (BAL) was found in all antibiotic-treated cases but in only two control cases. Perfusate endotoxin levels at 12 h were significantly lower in the antibiotic group compared with the control group. EVLP with broad-spectrum antibiotic therapy significantly improved pulmonary oxygenation and compliance and reduced pulmonary vascular resistance. Perfusate endotoxin levels at 12 h were strongly correlated with levels of perfusates tumor necrosis factor α, IL-1ß and macrophage inflammatory proteins 1α and 1ß at 12 h. In conclusion, EVLP treatment of infected donor lungs with broad-spectrum antibiotics significantly reduced BAL bacterial counts and endotoxin levels and improved donor lung function.

Impact of cytokine expression in the pre-implanted donor lung on the development of chronic lung allograft dysfunction subtypes.

The long-term success of lung transplantation continues to be challenged by the development of chronic lung allograft dysfunction (CLAD). The purpose of this study was to investigate the relationship between cytokine expression levels in pre-implanted donor lungs and the posttransplant development of CLAD and its subtypes, bronchiolitis obliterans syndrome (BOS) and restrictive allograft syndrome (RAS). Of 109 patients who underwent bilateral lung or heart-lung transplantation and survived for more than 3 months, 50 BOS, 21 RAS and 38 patients with No CLAD were identified by pulmonary function test results. Using donor lung tissue biopsies sampled from each patient, expression levels of IL-6, IL-1ß, IL-8, IL-10, interferon-γ and tumor necrosis factor-α mRNA were measured. IL-6 expression levels were significantly higher in pre-implanted lungs of patients that ultimately developed BOS compared to RAS and No CLAD (p = 0.025 and 0.011, respectively). Cox regression analysis demonstrated an association between high IL-6 expression levels and BOS development (hazard ratio = 4.98; 95% confidence interval = 2.42-10.2, p < 0.001). In conclusion, high IL-6 mRNA expression levels in pre-implanted donor lungs were associated with the development of BOS, not RAS. This association further supports the contention that early graft injury impacts on both late graft function and early graft function.

Neoadjuvant aortic endografting.

The advent and success of endovascular repair of abdominal aneurysms led to the development of catheter-based techniques to treat thoracic aortic pathology. Such diseases, including thoracic aortic aneurysms, acute and chronic type B dissections, penetrating aortic ulcers, and traumatic aortic transection, challenge surgeons to perform complex open operative repairs in high-risk patients. The minimally invasive nature of thoracic endografting provides an attractive alternative therapy. We present two cases of covered stent grafts deployed in the thoracic aorta to perform resection of the aortic wall infiltrated by malignancy in order to avoid a major vascular intervention and a traditional vascular graft interposition. This may become a potential new utility for aortic endografts.

mTOR inhibition induces endothelial progenitor cell death.

Immunosuppressants are necessary to prevent graft rejection after solid organ transplantation. However, they are also known to have significant side effects, including endothelial toxicity. Endothelial progenitor cells originate in the bone marrow and are recognized by their angiogenic and endothelial reparative properties. The effects of the immunosuppressants cyclosporine A (CyA), tacrolimus and rapamycin were analyzed on endothelial progenitor-like cells. Rapamycin induced rapid cell death, even at concentrations much lower than those used clinically, in peripheral blood mononuclear cells (PBMC) cultured to favor outgrowth of endothelial progenitors. Cyclosporine A and tacrolimus had no significant effects at clinical concentrations. The effect of rapamycin was specific to endothelial progenitor cells, in particular to the early stages of differentiation, as a lesser effect was observed in late outgrowth endothelial progenitors, mature aortic endothelial cells, and macrophages derived from the same PBMCs. The mechanism of cell death appeared to be apoptosis; however, its induction was probably multifactorial and did not depend on caspase or cathepsin activation. In conclusion, rapamycin induces endothelial progenitor cell death, possibly because it blocks survival signals given by growth factors critically required by these cells.

Pre-implantation multiple cytokine mRNA expression analysis of donor lung grafts predicts survival after lung transplantation in humans.

While current donor selection with clinical findings is generally effective, the imprecise nature of the assessment forces clinicians to remain on the conservative side. A reliable biological marker would assist donor selection and would improve donor organ utilization. We collected biopsies from 169 donor lungs before implantation. Expression levels of IL-6, IL-8, IL-10, TNF-alpha, IFN-gamma and IL-1beta were measured by quantitative real-time RT-PCR (qRT-PCR). Seventeen cases died within 30 days after transplantation. No donor factor was significantly associated with 30-day mortality. Univariate analysis of the 84 cases for development of the prediction model showed that IL-6, IL-8, TNF-alpha and IL-1beta were risk factors for mortality and IL-10 and IFN-gamma were protective factors. We analyzed the cytokine expression ratios of risk to protective cytokines. A stepwise logistic regression for 30-day mortality demonstrated that a model containing the ratio of IL-6/IL-10 was the most predictive (p = 0.0013). When applied to the remaining 85 cases for validation, the test of model fit was significant (p = 0.039). Using the cytokine ratio, we were able to define three risk groups with striking differences in survival (p = 0.0003). Multi-cytokine analysis of the donor lung graft with qRT-PCR shows significant promise as a strategy to biologically evaluate the donor lung prior to implantation.

Transbronchial administration of adenoviral-mediated interleukin-10 gene to the donor improves function in a pig lung transplant model.

Interleukin-10 (IL-10) gene transfection of donor lungs prior to transplantation is an attractive strategy to reduce ischemia-reperfusion induced lung injury. However, experimental data with gene therapy in large animal models of lung transplantation are generally lacking. We have developed a simple clinically applicable technique for adenoviral-mediated gene delivery of human IL-10 to the lung of large animals that provides homogenous gene expression after 12-24 h of transfection. Using this technique of gene delivery, we have studied the dynamics of adenoviral gene delivery to the lung in the setting of lung transplantation. Although there is a persistent inflammatory response to the adenoviral vector, we achieved significant expression of human IL-10 in lung tissue before lung retrieval to obviate the deleterious impact of the adenoviral vector on the donor lung. The administration of adenoviral-mediated human IL-10 to the donor lung reduced ischemia-reperfusion injury and improved graft function after lung transplantation in this pig lung transplantation model. Transfection of adenoviral-mediated human IL-10 to the donor lung prevented the release of inflammatory cytokines such as IL-6 in lung tissue and plasma. We have demonstrated that IL-10 gene therapy has significant potential to prevent or treat the inflammatory response associated with ischemia-reperfusion injury in lung transplantation. In the future, IL-10 gene therapy could also be used for immunomodulation or tolerance induction.

The influence of lung volume reduction surgery on exercise in patients with COPD.

Although the influence of lung volume reduction surgery (LVRS) on incremental- and constant-power exercise is important in the evaluation of this procedure for patients with chronic obstructive pulmonary disease (COPD), it is rarely reported even in large randomised controlled trials. This report describes 39 patients with severe COPD ((mean +/- SE) forced expiratory volume in one second 32 +/- 2% pred, functional residual capacity 195 +/- 6% pred) who participated in a randomised controlled trial of LVRS and who completed incremental exercise tests at 6 months as well as endurance tests (constant power of 25 +/- 1 W) at 3, 9 and 12 months. Peak oxygen uptake (V'O2,pk) was similar between the treatment (n = 19) and control groups (n = 20) at baseline. After LVRS, the treatment group had a significantly greater V'O2,pk (mean difference (95% CI) 1.28 (0.07-2.50) mL x kg x min(-1)) and power (13 (6-20) W). The treatment group achieved a significantly greater minute ventilation (7.1 (2.9-11.3) L x min(-1)) with a greater tidal volume (0.16 (0.04-0.28) L). Baseline endurance was similar between groups. After surgery, there were significant between-group differences in endurance time, which were maintained at 12 months (7.3 (3.9-10.8) min). Lung volume reduction surgery is associated with an increase in exercise capacity and endurance, as compared with conventional medical treatment.

Influence of lung volume reduction surgery (LVRS) on health related quality of life in patients with chronic obstructive pulmonary disease.

BACKGROUND: The clinical value of LVRS has been questioned in the absence of trials comparing it with pulmonary rehabilitation, the prevailing standard of care in COPD. Patients with heterogeneous emphysema are more likely to benefit from volume reduction than those with homogeneous disease. Disease specific quality of life is a responsive interpretable outcome that enables health professionals to identify the magnitude of the effect of an intervention across several domains. METHODS: Non-smoking patients aged <75 years with severe COPD (FEV(1) <40% predicted, FEV(1)/FVC <0.7), hyperinflation, and evidence of heterogeneity were randomised to surgical or control groups after pulmonary rehabilitation and monitored at 3 month intervals for 12 months with no crossover between the groups. The primary outcome was disease specific quality of life as measured by the Chronic Respiratory Questionnaire (CRQ). Treatment failure was defined as death or functional decline (fall of 1 unit in any two domains of the CRQ). Secondary outcomes included pulmonary function and exercise capacity. RESULTS: LVRS resulted in significant between group differences in each domain of the CRQ at 12 months (change of 0.5 represents a small but important difference): dyspnoea 1.9 (95% confidence interval (CI) 1.3 to 2.6; p<0.0001); emotional function 1.5 (95% CI 0.9 to 2.1; p<0.0001); fatigue 2.0 (95% CI 1.4 to 2.6; p<0.0001); mastery 1.8 (95% CI 1.2 to 2.5; p<0.0001). In the control group one of 27 patients died and 16 experienced functional decline over 12 months. In the surgical group four of 28 patients died and three experienced functional decline (hazard ratio = 3.1 (95% CI 1.3 to 7.6; p=0.01). Between group improvements (p<0.05) in lung volumes, flow rates, and exercise were sustained at 12 months (RV -47% predicted (95% CI -71 to -23; p=0.0002); FEV(1) 0.3 l (95% CI 0.1 to 0. 5; p=0.0003); submaximal exercise 7.3 min (95% CI 3.9 to 10.8; p<0.0001); 6 minute walk 66 metres (95% CI 32 to 101; p=0.0002). CONCLUSIONS: In COPD patients with heterogeneous emphysema, LVRS resulted in important benefits in disease specific quality of life compared with medical management, which were sustained at 12 months after treatment.

Management of lung transplant recipients with bronchogenic carcinoma in the native lung.

Experience with lung transplantation for bronchogenic carcinoma is limited. In our experience, 3 of 6 patients died of recurrent carcinoma within 5 to 35 months after transplantation. Hence, we currently do not support lung transplantation for patients with pre-transplant diagnosis of bronchogenic carcinoma, with the exception of bronchioloalveolar carcinoma (BAC) confined to the lung. Patients with BAC should be staged thoroughly with chest and abdominal computerized tomography, brain magnetic resonance imaging, and bone scan repeated every 3 months while on the waiting list, and should undergo mediastinoscopy at the time of transplantation, with a plan for a backup recipient if metastatic lymph nodes are detected. Proposal for lung transplantation for patients with bronchogenic carcinoma, with the exception of BAC, probably should be performed in the setting of a clinical trial developed with input from the lung transplant community.

Prostaglandin E1 protects lung transplants from ischemia-reperfusion injury: a shift from pro- to anti-inflammatory cytokines.

INTRODUCTION: Prostaglandin E1 (PGE1) has been demonstrated to reduce ischemia-reperfusion (IR) injury following lung transplantation. However, the cytoprotective mechanisms remain largely unknown. The purpose of this study was to determine whether the mechanism through which PGE1 improves IR injury is related to the level of apoptosis or the release of inflammatory cytokines. METHODS: In a rat single-lung-transplant model, animals were randomly allocated into four groups of five animals each. Group 1 received normal saline (NS) in the preservation solution and during the 2-hr reperfusion period. Group 2 received NS in the preservation solution and PGE1 during the reperfusion period. Group 3 received PGE1 in the preservation solution and NS during the reperfusion period. Group 4 received PGE1 in the preservation solution and during the reperfusion period. RESULTS: The two groups that received PGE1 during the reperfusion period had a significantly higher partial pressure of oxygen (PaO2), lower wet-dry weight ratio, and lower peak airway pressure at the end of the reperfusion period than did the two groups that received NS. In the two groups that received PGE1 during the reperfusion period, we observed significantly higher levels of interleukin (IL)-10 in the transplanted lung tissue and plasma and significantly lower levels of tumor necrosis factor (TNF)-alpha, interferon (IFN)-gamma, and IL-12 in lung tissue. The levels of IL-4 and macrophage inflammatory protein-2 (MIP-2) were not significantly different between groups. The number of apoptotic cells and the expression of Bcl-2 were not significantly different between groups. CONCLUSIONS: PGE1 does not decrease the amount of apoptosis after reperfusion and does not significantly upregulate Bcl-2. We have demonstrated that PGE1 administered during the reperfusion period reduces IR injury and improves lung function through a mechanism that is likely mediated by a shift between pro- and anti-inflammatory cytokine release.

Carotid pressure is a better predictor of coronary artery disease severity than brachial pressure.

The mechanisms relating pulse pressure to cardiovascular outcome may include surrogacy for coronary disease severity. Although pulse pressure is typically measured at the brachial artery, central pulse pressure and its principal determinant, large-artery stiffness, may relate more closely to disease severity. This study aimed to determine the relationships between large-artery stiffness and carotid and brachial blood pressures and coronary artery disease severity. One hundred fourteen male patients with coronary artery disease (age 60+/-8 years, mean+/-SD) and 57 age-matched healthy male controls (age 59+/-9 years) were recruited. Patients were classified into 2 groups based on the magnitude of their maximum coronary stenosis: moderate (50% to 89%) and severe (>/=90%). Large-artery stiffness was assessed as systemic arterial compliance and carotid-femoral pulse wave velocity. Mean pressure was not different between the 3 groups. Systemic compliance and carotid pulse pressure were significantly different between all 3 groups, with compliance lowest and pressure highest in the severe group (P<0.05). Pulse wave velocity was higher in patients with severe stenosis than in those with moderate stenosis (P<0.01) and those in the control group (P<0.001). Brachial pulse pressure was higher in patients than in controls (P<0.05), but there was no difference between the 2 disease groups. In separate multivariate analyses, carotid pressures and systemic arterial compliance were determinants of coronary artery disease severity, independent of age, smoking status, body mass index, mean arterial pressure, heart rate, cholesterol levels (total, LDL, and HDL), triglycerides, and beta-antagonist and lipid-lowering therapy (P<0.001), whereas brachial pressures and pulse wave velocity were not. In conclusion, central blood pressures and systemic arterial compliance are more sensitive markers of coronary artery disease severity than brachial pressures.

Withdrawal of hormonal therapy for 4 weeks decreases arterial compliance in postmenopausal women.

BACKGROUND: We demonstrated in a previous cross-sectional study that arterial compliance is elevated in postmenopausal women taking estrogen-containing hormonal therapy, which may partially account for the reduction in cardiovascular risk observed. OBJECTIVE: To investigate the effects of withdrawal and recommencement of hormonal therapy, each for 4 weeks, on arterial compliance. METHODS: Seventeen postmenopausal women [aged 56 +/- 4 years (mean +/- SD)] taking long-term hormonal therapy (+HT group) were studied at baseline, 4 weeks after withdrawal of hormonal therapy and again 4 weeks after recommencement. Systemic arterial compliance (SAC), pulse wave velocity (PWV) in the aorto-femoral and femoral-dorsalis pedis regions, and hemodynamic variables were measured at baseline, and at the end of each study intervention. As a time-control, seventeen postmenopausal women (aged 63 +/- 7 years) not taking hormonal therapy (-HT group) were also investigated. RESULTS: SAC significantly decreased from 0.47 +/- 0.06 to 0.40 +/- 0.05 arbitrary compliance units (mean +/- SEM; P < 0.05) after 4 weeks withdrawal from hormonal therapy. PWV in the femoral-dorsalis pedis region was elevated significantly by the withdrawal of hormonal therapy (8.4 +/- 0.4 to 9.4 +/- 0.5 m/s; P < 0.05), but PWV in the aortofemoral region did not change. After therapy had been recommenced for 4 weeks, SAC and PWV in the femoral-dorsalis pedis region were restored to baseline values. The -HT group showed no difference in SAC or PWV, and mean arterial pressure did not change in either group throughout the study period. CONCLUSION: These data suggest that hormonal modulation of distal arterial vascular tone may account for short-term changes in arterial compliance associated with estrogen-containing hormonal therapy.

Lung transplantation for chronic obstructive pulmonary disease.

Emphysema is the fifth leading cause of death in North America. It is now the most common indication for lung transplantation worldwide. Since 1986, evolution in operative techniques and improvements in organ preservation and post-operative immunosuppression have resulted in impressive long-term survival results. Significant problems remain in terms of inadequate organ supply and chronic rejection; many more candidates could be transplanted if not for these two major limitations. However, other options are now available for the surgical management of patients with end-stage emphysema. The decision making surrounding transplantation for emphysema has been radically altered by the advent of lung volume reduction surgery. This review will highlight new data that pertains to recipient and donor selection, choice of transplant procedure, either single or bilateral, and the role of lung volume reduction surgery. At the University of Toronto we generally favour bilateral lung transplantation for superior functional results and possibly enhanced long-term survival. We have been particularly interested in combining lung transplantation with synchronous lung volume reduction surgery and the rationale and results of this procedure are reviewed.

Major histocompatibility complex expression and lung ischemia-reperfusion in rats.

BACKGROUND: Clinical studies in kidney and liver transplantation have suggested that poor early function is associated with increased graft loss due to rejection. Ischemia-reperfusion injury may contribute to rejection by enhancing graft immunogenicity. METHODS: A rat model of unilateral in situ pulmonary ischemia-reperfusion was used to examine class II major histocompatibility complex (MHC) antigen expression. The effects of deflation during ischemia (which augments subsequent injury) as well as concurrent allostimulation were also examined. Major histocompatibility complex expression was examined 9 days after ischemia using the binding of radiolabeled anti-class II antibody and immunohistochemistry. RESULTS: Four hours of ischemia in full inflation or 2 hours of atelectatic ischemia both led to severe lung injury. Ischemia-reperfusion injury led to greater MHC expression in the ischemic lung compared with the nonischemic side. Allostimulation with mononuclear cells did not increase MHC expression in the nonischemic lung but did enhance the increase found in the ischemic lung. This was not due to a graft-versus-host response because allostimulation with F1 cells also led to a significant increase. CONCLUSIONS: Severe ischemic lung injury leads to significant increases in MHC expression, detectable after 9 days of reperfusion. Deflation during ischemia, which augments lung injury, also augments increased MHC expression. Concurrent allostimulation with foreign mononuclear cells appears to potentiate increased MHC expression after ischemia. Increases in graft MHC expression may enhance immunogenicity and increase the rejection response.

Intracellular pH regulation during spreading of human neutrophils.

The regulation of the intracelluar pH (pHi) during spreading of human neutrophils was studied by a combination of fluorescence imaging and video microscopy. Spreading on adhesive substrates caused a rapid and sustained cytosolic alkalinization. This pHi increase was prevented by the omission of external Na+, suggesting that it results from the activation of Na+/H+ exchange. Spreading-induced alkalinization was also precluded by the compound HOE 694 at concentrations that selectively block the NHE-1 isoform of the Na+H+ antiporter. Inhibition of Na+/H+ exchange by either procedure unmasked a sizable cytosolic acidification upon spreading, indicative of intracellular acid production. The excess acid generation was caused, at least in part, by the activation of the respiratory burst, since the acidification closely correlated with superoxide production, measured in single spreading neutrophils with dihydrorhodamine-123, and little acid production was observed in the presence of diphenylene iodonium, a blocker of the NADPH oxidase. Moreover, neutrophils from chronic granulomatous disease patients, which do not produce superoxide, failed to acidify. Comparable pHi changes were observed when beta 2 integrins were selectively activated during spreading on surfaces coated with anti-CD18 antibodies. When integrin engagement was precluded by pretreatment with soluble anti-CD18 antibody, the pHi changes associated with spreading on fibrinogen were markedly reduced. Inhibition of microfilament assembly with cytochalasin D precluded spreading and concomitantly abolished superoxide production and the associated pHi changes, indicating that cytoskeletal reorganization and/or an increase in the number of adherence receptors engaged are required for the responses. Neutrophils spread normally when the oxidase was blocked or when pHi was clamped near physiological values with nigericin. Spreading, however, was strongly inhibited when pHi was clamped at acidic values. Our results indicate that neutrophils release superoxide upon spreading, generating a burst of intracellular acid production. The concomitant activation of the Na+/H+ antiport not only prevents the deleterious effects of the acid released by the NADPH oxidase, but induces a net cytosolic alkalinization. Since several functions of neutrophils are inhibited at an acidic pHi, the coordinated activation of pHi regulatory mechanisms along with the oxidase is essential for sustained microbicidal activity.

Intracellular signaling in neutrophil priming and activation.

In order for neutrophils to function effectively in host defense, they have evolved specific attributes including the ability to migrate to the site of inflammation and release an array of toxic products including proteolytic enzymes, reactive oxygen species, and cationic proteins. While these compounds are intended for killing invading pathogens, if released inappropriately, they may also contribute to tissue damage. Such inflammatory tissue injury may be important in the pathogenesis of a variety of clinical disorders including arthritis, ischemia-reperfusion tissue injury, the systemic inflammatory response syndrome (SIRS), and the acute respiratory distress syndrome (ARDS). Despite the importance of neutrophil function in host defense and dysfunction in disease states, much remains unknown about the intracellular signaling pathways regulating neutrophil activity. This review will focus on the signaling molecules regulating leukocyte 'effector' functions including receptors, GTP-binding proteins, phospholipases, polyphosphoinositide metabolism, and protein kinases and phosphatases.

Current techniques in cell and molecular biology.

Recent advances in the field of molecular biology have revolutionized our understanding of the functioning of living organisms and facilitated the development of robust tools for both diagnosis and treatment of diseases. With particular reference to the field of critical care medicine, development of molecular biology techniques have aided in the following: (1) rapid and highly specific detection of pathogenic infectious agents (eg, Mycobacterium tuberculosis, Pneumocystis carinii, cytomegalovirus, Legionella); (2) development of assays for measurement of circulating cytokines such as tumor necrosis factor (TNF) and interleukin (IL)-1 that has helped our understanding of the pathogenesis of the sepsis syndrome; (3) administration of antibodies or soluble receptors to attempt to prevent untoward effects of cytokines such as TNF or IL-1; and (4) the administration of recombinant deoxyribonucleic acid (DNA) or proteins to patients in an attempt to alter the course of a disease such as antioxidant enzymes (superoxide dismutase). The rapidity of progress in this field has been staggering, which necessitates frequent updating of our knowledge for clinicians to put these molecular tools to their best use. This brief review attempts to explain the basic principles of commonly used techniques in molecular biology including recombinant DNA, polymerase chain reaction, DNA libraries, gene therapy, and protein biochemistry in a manner that is understandable to those without an in-depth knowledge of the field.

Antimicrobial prophylaxis in surgery. Committee on Antimicrobial Agents, Canadian Infectious Disease Society.

OBJECTIVE: To provide guidelines for antimicrobial prophylaxis on the basis of the type of surgical procedure. OPTIONS: Standard drug regimens for prophylaxis of infection in a variety of surgical procedures were considered, including a first-generation cephalosporin; an aminoglycoside in combination with metronidazole, clindamycin or erythromycin; a second-generation cephalosporin; and trimethoprim-sulfamethoxazole. OUTCOMES: In order of importance: efficacy, side effects and cost. EVIDENCE: A MEDLINE search of articles published between January 1980 and December 1991. For clinical trial data, greatest emphasis was placed on randomized, double-blind studies using appropriate controls. VALUES: The Committee on Antimicrobial Agents of the Canadian Infectious Disease Society (CIDS) and two recognized experts (T.K.W. and O.D.R.) recommended antimicrobial regimens suitable for prophylaxis of infections in surgery. Whenever possible, recommendations were based on data from randomized controlled trials. BENEFITS, HARMS AND COSTS: Implementation of the guidelines is expected to reduce the incidence of postoperative infections, the inappropriate use of antibiotics and costs to hospitals. RECOMMENDATIONS: Antibiotic prophylaxis is recommended for operations with a high risk of postoperative wound infection or with a low risk of infection but significant consequences if infection occurs. These operations include clean-contaminated procedures and certain clean procedures. Drugs should be administered intravenously immediately before the operation. In colorectal operations oral administration also appears to be effective. A single dose is sufficient for most procedures. The regimen chosen depends on the pathogens usually associated with wound infection in a given operation, the serum half-life of the drugs, the antimicrobial susceptibility patterns in the local hospital and the cost of the drugs. VALIDATION: The guidelines were compared with others in standard textbooks of surgery and peer-reviewed articles. The guidelines were prepared and revised by the Committee on Antimicrobial Agents of the CIDS. They were then reviewed and revised further by the Council of the CIDS. SPONSOR: The CIDS was solely responsible for developing, funding and endorsing these guidelines.