Infectious Disorders - Drug Targets - Volume 10, Issue 1, 2010

Acute pancreatitis is a dynamic, evolving process with a two distinctly different clinical phases of the evolution of the disease. Mild disease is also called interstitial pancreatitis and the clinical features of this entity is strongly related to the inflammatory process and the acute -phase proteins released from the liver. In the other side of the spectrum, severe disease is defined as involving either a local or systemic complication. In the early phase usually within the first week the severity is related to organ failure due to SIRS (systemic inflammatory response) but local or systemic infection is not present. In the second phase the disease either resolves or progress to necrotizing pancreatitis with changes in the pancreatic morphology. This phase last weeks to months and it is related to the necrotizing process. Mortality in this second protracted phase is correlated with infection of pancreatic necrosis. Morphologic criteria and presence of local or systemic complications are applied to determine severity of the inflammatory process and are used potentially to treatment selection. Infected pancreatic necrosis is a secondary infection of the pancreas and peri-pancreatic tissues affecting 40-70% of patients with severe disease in the late phase. Infected necrosis is located retroperitonealy and usually extends towards the paracolic gutters. It occurs by bacteria spread from the gastrointestinal tract, biliary tree or by iatrogenic intervention. Depending on the stage of the necrosis and the organism involved, the infected pancreatic necrosis will have varying amounts of suppuration. In the later stages, the content may be predominantly pus as the process of liquefaction necrosis matures. The presence of infection can be presumed based on the appearance of gas within the area of infected pancreatic or peri-pancreatic necrosis in the non-enhancing area on Computing Tomography. However diagnosis can be established based only by image-guided, fine needle aspiration (FNA) with a Gram positive stain or culture. Distinction between sterile and infected necrosis is important, because the presence of infection confers a different natural history, prognosis and management. Patients with infection require active intervention by means of operative, percutaneous or endoscopic necrosectomy. Attempts to reduce mortality in acute pancreatitis, by preventing infectious complications with prophylactic antibiotics or probiotics are promising although much controversy exists. Recently bacteremia is considered as a prognostic marker to raise the level of suspicion for infected necrosis. It is also clear that half of relevant infections occur in the first few days of acute pancreatitis providing support to the concept of early antibiotic prophylaxis. Recent randomized trials of antibiotic prophylaxis, commencing treatment in the first 72-120 h after onset of symptoms. Results from a recent randomized trial showing a significant reduction in extrapancreatic sepsis by starting antibiotic prophylaxis on admission to hospital, support this suggestion. In addition antibiotics on admission and early enteral nutrition are attractive options for randomized trials. Enteral nutrition is of paramount importance in the early prevention of pancreatic infection and minimizes the risk of antibiotic-resistant bacteria and fungi as a result of antibiotic prophylaxis. In this supplement a focus in both pathophysiology of infection in acute pancreatitis and a thorough review of the literature regarding prevention and treatment of infected necrosis from the prospect of experts in pancreatic surgery is performed.

Two key pathologic acinar cell responses of acute pancreatitis are vacuole accumulation and trypsinogen activation. Degradation of long-lived proteins, a measure of autophagic efficiency, is markedly inhibited in pancreatitis. Further, processing of the lysosomal proteases cathepsin L (CatL) and CatB into their fully active, mature forms is reduced in pancreatitis, as are their activities in the lysosome-enriched subcellular fraction. These findings indicate that autophagy is retarded in pancreatitis due to deficient lysosomal degradation caused by impaired cathepsin processing. Trypsinogen activation occurred in pancreatitis and is prevented by inhibiting autophagy. A marker of trypsinogen activation partially localized to autophagic vacuoles, and pharmacologic inhibition of CatL increased the amount of active trypsin in acinar cells. The results suggest that retarded autophagy is associated with an imbalance between CatL, which degrades trypsinogen and trypsin, and CatB, which converts trypsinogen into trypsin, resulting in intra-acinar accumulation of active trypsin in pancreatitis. Thus, deficient lysosomal degradation may be a dominant mechanism for increased intra-acinar trypsin in pancreatitis. Proinflammatory cytokines and oxidative stress play a pivotal role in the early pathophysiological events of the disease. Cytokines such as interleukin 1beta and tumor necrosis factor alpha initiate and propagate almost all consequences of the systemic inflammatory response syndrome. On the other hand, depletion of pancreatic glutathione is an early hallmark of acute pancreatitis and reactive oxygen species are also associated with the inflammatory process. Changes in thiol homestasis and redox signaling decisively contribute to amplification of the inflammatory cascade through mitogen activated protein kinase (MAP kinase) pathways.

Infected necrotizing pancreatitis is the most severe form of acute pancreatitis and is related with high rates of morbidity and mortality. The close cooperation and communication, working as a team, among interventional radiologists surgeons and gastroenterologists improves the successful treatment considerably. Therapeutic modalities such as percutaneous CT-guided catheter drainage can be helpful to save lives, changing dramatically the clinical aspect of the patient. The objective of this paper is to review the indications and techniques of image-guided percutaneous treatment of pancreatic infected pseudocysts and to report our clinical experience and observations made during primary CT-guided percutaneous catheter drainage of infected abscesses.

Severe acute pancreatitis is a potentially life-threatening disease. Pancreatic necrosis is associated with an aggravated prognosis, while superimposed infection is almost always lethal without surgery. Bacterial translocation mainly from the gut is the most widely accepted mechanism in the pathogenesis of infected pancreatic necrosis. Infected pancreatic necrosis should be suspected in the presence of the usual markers of systemic inflammation (i.e., fever and leukocytosis), organ failure, or a protracted severe clinical course. The diagnostic method of choice to confirm the diagnosis of pancreatic necrosis is contrast-enhanced computed tomography, where necrotic areas are evidenced as regions without enhancement. The presence of pancreatic necrotic infection should be based on a combination of clinical manifestations, results of laboratory investigation (mainly increased levels of CRP and / or procalcitonin), and can be confirmed by image-guided fine-needle aspiration and gram stain /culture of the aspirates. Surgery remains the treatment of choice for the management of infected pancreatic necrosis and involves open necrosectomy (debridement) and wide drainage of the peripancreatic areas, often in association with continuous irrigation. Planned reoperations may be required to achieve complete removal of the necrotic / infected material. The timing of surgery is of paramount importance; ideally, surgery should be performed after 2 or 3 weeks from the onset of pancreatitis. Recently, various minimally invasive approaches have been described, but they have not been compared in prospective trials with the classical open surgery. Antibiotic therapy is routinely used in patients with infected necrotizing pancreatitis, in conjunction with surgical debridement; its role, however, in the management of patients with sterile necrosis is recently questioned. Nutritional support should be taken into consideration in these patients; enteral nutrition should be preferred over total parenteral nutrition to improve the anatomical and functional integrity of the gut mucosa, thereby preventing bacterial translocation.

Acute pancreatitis affects around 40 per 100.000 of the general population and 20-30% of attacks are severe. Mortality is usually associated to septic multiorgan dysfunction syndrome caused by secondary infection of pancreatic or peripancreatic necrosis. The diagnosis of acute pancreatitis is generally based on clinical and laboratory findings. However CT is the imaging technique of choice for detecting complications. Patients with complicated pancreatitis require multiple follow-up examinations. Substitution of US or MRI for CT in certain cases would reduce the radiation dose considerably. Complicated pseudocysts and other pancreatic collections may contain solid debris, which is best depicted by MRI. Abscesses are suggested when gas is present in a pancreatic or peripancreatic collection. MRI can reveal air-fluid levels or large pockets of gas, but CT is more sensitive for small gas collections. US or CT-guided percutaneous drainage of pancreatic abscesses or infected collections is a useful therapeutic approach in acute cases obviating the need for unnecessary surgery. On the other hand infected necrosis can not be successfully treated percutaneously due to its thicker consistency. In this review, the role of different imaging modalities in the evaluation of post-pancreatitis infection as well as in the treatment planning will be discussed.

The diagnosis of IE is frequently supported by an assemblage of clinical findings rather than a sole definitive test result. The diagnosis usually becomes apparent when there are several positive blood cultures in the occurrence of a documented underlying cardiac defect. Nevertheless, some IE patients do not have positive blood cultures and approximately 25 to 30 % of patients have no recognizable underlying cardiac lesions at the onset of the disease. Keeping that in mind along with the fact that the disease may be present with atypical features, the physicians may avoid unnecessary delays in establishing a diagnosis and promptly introduce the appropriate treatment modalities. The overall incidence of infective endocarditis is 1.7 to 4.0 per 100,000 population and in adults older than 50 years, it exceeds 15 per 100,000 population. However, the precise incidence of IE is difficult to be determined because case definitions have diverged from decade to decade, among different authors, and among different medical facilities. Furthermore, the incidence of predisposing conditions (e.g., rheumatic heart disease and injection drug use) has wandered over time and among different areas. Sex and age have an impact on the incidence of IE with men prevailing in most series, and almost 50-60% of cases of acute IE do not necessitate an underlying heart condition to be present. The microorganisms most accountable for the development of acute IE (e.g. S. aureus) are exceedingly virulent and able to colonize normal heart valves. Nowadays, the incidence of acute IE has been progressively increasing and surpasses the number of subacute IE cases. Elderly patients or those with congenital heart defects, rheumatic heart disease, immunosuppression, AIDS, intravenous drug abuse (IVDA) and patients with a malignancy are more vulnerable to IE. Mitral valve prolapse comprises the most common (30%) predisposing condition found in young adults, and bicuspid aortic valve is the most common underlying congenital condition (15%). Rheumatic heart disease currently accounts for less than 20% of cases, but 6% of these patients develop IE in their lifetimes. In 75% of cases of IVDA IE, no underlying valvular abnormalities are noted, and 50% of them involve the tricuspid valve. Prosthetic valve endocarditis (PVE) accounts for 10-20% of all cases of IE, and in the long run, 5% of mechanical and bioprosthetic valves become infected. Mechanical valves are more likely to be infected within the first 3 months of implantation, and bioprosthetic valves are more likely to be infected after the first year. The mitral valves are more vulnerable than those in the aortic area. Analogous to PVE are infections of implantable pacemakers (PMs) and cardioverter -defibrillators. Usually, these devices are infected within a few months of implantation. The principle causative agents include Streptococcus viridans (55%), Staphylococcus aureus (30%), Enterococcus (6%) and HACEK bacteria, although on occasions it can also be caused by fungi. Earlier than the accessibility of antimicrobial regimens, IE was consistently lethal. Nowadays, roughly 80 % of IE patients will survive from this infection, but in the same time one out of every six IE patients will succumb during their initial hospitalization, and when highly virulent agents (such as S. aureus) are implicated almost 30% of these patients may not survive as a direct or indirect result of their valvular infection. It should also be noted that an unfavourable outcome in these patients may arise regardless of the timely institution of the appropriate antimicrobial treatment and in spite of the dexterous implementation of contemporary diagnostic procedures. Antibiotics are usually administered intravenously for 2-6 weeks and duration usually depends on the pathogen's virulence. Fifteen to twentyfive percent of IE patients are treated surgically. Surgery was not introduced in the management of IE until 1961, but during the last decades, valve replacement or repair have become everyday practice when confronting with certain complications of IE. Moreover, the decline in mortality from IE has been attributed to the amalgamation of appropriate antibiotic treatment and judicious surgical approach. The removal of an infected valve is necessary when antibiotic therapy fails, there are persistent vegetations after systemic embolization or vegetations increase their size after antimicrobial treatment, in valvular dysfunction and in fungal endocarditis. Complications, including metastatic abscesses, are common. The mortality rate of IE is 25%. The risk of death increases with the occurrence of complications, and mortality rates as high as 40% are observed with S. aureus infective endocarditis. Even though there are no prospective randomized trials which have proven that prophylactic antibiotic administration for preventing bacterial endocarditis is beneficial, this approach has become standard in most developed countries. To our opinion, it is rather improbable that such a trial will ever be carried out, known the exceptionally low incidence of IE following procedures such as dental surgery and also the medical ethics and legal environment in the United States and Europe. In the present mini hot topic the authors have focused on the current prevention guidelines, the major issues related to the antimicrobial therapy and the effectiveness, indications for, and outcomes of surgery in IE. The clinical characteristics and management of IE, including aspects of IE that are distinctive to or typical of patients, who are injecting illicit substances, will also be reviewed here. Finally, there a special review article concerning Q fever endocarditis which represents the most severe and frequently lethal appearance of chronic Q fever.

Infective endocarditis (IE) is not the most frequent infection acquainted in intravenous drug abusers (IVDAs). On the other hand, all physicians should keep a high index of suspicion and always consider this possibility when they are dealing with an infectious process in this special population group. Since Sir William Osler, at the turn of the previous century, first described IE, there have been tremendous alterations in the very nature of this serious and possibly fatal disease. Right-sided endocarditis accounts for almost 10% of all IE episodes and has been correlated most commonly with injection of illicit drugs. However, recent reports have proposed that left-sided valves' participation is seen more often now than in the past. Although, the advances in medicine and especially modern imaging techniques have expanded our capacity to identify IE, there are still some gray areas in our ability to fully comprehend right-sided IE. Hussey et al. [1] were the first to distinguish IE as a distinct impediment of IV narcotics abuse in 1950. Although, many reports have been published since then arguing about the aspects of this medical entity, we will try here to comprehensively review the epidemiology and predisposing factors, clinical features and complications, diagnosis, treatment and prognosis of this disease, emphasizing on those distinctive or exclusive features seen in IE patients who are injecting illicit substances.

Coxiella burnetii, the agent of Q fever, produces a variety of clinical syndromes. The most frequent and serious chronic presentation is endocarditis, which presents unspecifically as a blood-culture negative endocarditis. It occurs almost exclusively in patients who have pre-existing valvular disease or who are immunocompromised. Without prompt recognition and appropriate antimicrobial therapy, the course of Q fever endocarditis is severe and potentially fatal. The epidemiology, signs and symptoms, laboratory findings, diagnosis and treatment of Q fever endocarditis are presented in our review.

Despite medical advances, the mortality in infective endocarditis is today very high. Its clinical and epidemiological characteristics are changing over time, with more elderly patients affected, with more underlying comorbidities and with Staphylococci as the most frequent pathogen. Effective treatment in complicated cases needs a multidisciplinary approach, and surgery is necessary in 40-50% of cases. Since clinical trials are difficult to be conducted in infective endocarditis, the scientific evidence is weak. The main indications of surgical treatment are heart failure due to valvular regurgitation and uncontrolled infection because of periannular extension or difficult-to-treat micro-organisms. Prospective analysis has demonstrated that medical-surgical treatment is better than only medical treatment in complicated endocarditis with severe cardiac failure but mortality is still high with periannular extension. Prosthetic endocarditis has better prognosis with surgical treatment in the presence of complications and when the aetiology is S aureus. In patients without extensive non-hemorrhagic neurological lesions, early surgical intervention is safe. Mitral repair is nowadays an effective surgical technique when there is not extensive valve destruction, since replacement with a prosthetic valve has several problems like risk of infection, requirement for anticoagulation and durability. There is no evidence that the employment of homografts is better than aortic valve replacement, and the most important issue is the complete removal of the infected tissue. The pacemaker and defibrillator infection is best treated by removal of the device and the leads along with effective antibiotic therapy. Percutaneous lead extraction is the method of choice, and surgery is reserved only when there are contraindications or failure of the percutaneous techniques, large vegetations, and tricuspid regurgitation. Whenever is possible, tricuspid repair, is preferable, but replacement must be considered when there is a chance for recurrence after repair.

Previous to the availability of antimicrobial therapy, infective endocarditis (IE) was habitually lethal. Although approximately 80 percent of patients with endocarditis currently survive their infections, one of every six patients with IE does not survive the initial hospitalization, and up to one-third of patients infected with highly virulent organisms (such as Staphylococcus aureus) may die as a direct or indirect result of their valvular infection. An unfavourable outcome in these patients can occur despite having received appropriate antimicrobial therapy in a suitable approach, and despite the expert use of modern diagnostic techniques. Our purpose is to review the main issues related to the antimicrobial therapy.

Indications of endocarditis prophylaxis have changed in the past years, because of the absence of any evidence that justified its use. The last guidelines only recommend prophylaxis in patients with underlying cardiac conditions with the higher risk of adverse outcomes, including patients with a previous history of infective endocarditis, patients with prosthetic heart valve or prosthetic material used for valve repair, patients with a valvulopathy after cardiac transplantation, and patients with an specific congenital heart disease. The list of procedures in which prophylaxis is necessary has been limited too. Nowadays it is recommended in patients who undergo any dental procedure that involves the gingival tissues or periapical region of a tooth and for those invasive procedures of the oral cavity or an invasive procedure of the respiratory tract that involves incision or biopsy of the respiratory mucosa. In this revision we try to expose the recent tendencies recommended by the international guidelines.