Flaviviridae family, including hepatitis C virus (HCV) and several flaviviruses. Devoid of an appropriate lipid biosynthetic machinery of their own, these single-strand positive-sense RNA viruses can induce dramatic changes in host metabolic pathways to establish a favorable environment for viral multiplication and acquire essential components to facilitate their assembly and traffic. Here we have reviewed the current knowledge on the intracellular life cycle of those from the Flaviviridae family, with particular emphasis on HCV and dengue virus (DENV), and their association with the biosynthesis and metabolism of LDs, with the aim to identify potential antiviral targets for development of novel therapeutic interventions.Lipid droplets (LDs) are endoplasmic reticulum (ER)-related dynamic organelles that store and regulate fatty acids and neutral lipids. They play a central role in cellular energy storage, lipid metabolism and cellular homeostasis. It has become evident that viruses have co-evolved in order to exploit host lipid metabolic pathways. This is especially characteristic of the  Cellular homeostasis is maintained by a constant metabolic energy flux. As one of the major energy sources, lipids are synthesized, modified and utilized through various pathways. Lipid droplets (LDs) are ubiquitous and conserved cytoplasmic compartments delineated by a phospholipid monolayer, and serve as energy reservoirs in almost all living organisms. Excess lipids are packaged, stored and distributed in LDs, an organelle which is not only important in lipid storage and metabolism, but protein quality control, pathogenesis, and immune responses  for completing their intracellular replication cycles. Hepatitis C virus (HCV) has long been demonstrated to do so   and cholesterol esters (CEs)  are converted into TAGs and stored in LDs. TAGs can be further hydrolyzed to generate DAGs or phosphatidic acid (PA) for membrane phospholipid synthesis and free fatty acids (FFAs) for energy production  pathway  which co-ordinate the hydrolysis of TAGs for energy production , Flavivirus , Pegivirus, and Pestivirus.Viruses of the Persistent infection with HCV in humans can develop into serious liver diseases, including fibrosis and liver cirrhosis, which could further progress into hepatocellular carcinoma  proteins   are derived from the ER  Wang, .A model proposed by Randall and Heaton suggested that DENV infection triggers lipophagy to deplete LDs, releasing FFAs. DENV also induces cellular β-oxidation to consume the FFAs released from lipophagy for energy production. Exogenously supplemented FAs can replace the need for lipophagy during DENV replication, suggesting that flaviviruses manipulate cellular lipid metabolism to create an environment that favors virus replication —a TAG-rich lipoprotein. For hijacking VLDL secretion, HCV inhibits the function of the putative TAG lipase, arylacetamide deacetylase (AADAC), thus, further impairing TAG lipolysis  protein with the host membrane. Blocking virus entry via targeting the viral E protein offers a means to suppress the onset of infection. A few heterocyclic compounds, such as compound 6, NITD-448 and P02, have been identified to directly bind to the hydrophobic pocket of viral E protein and block its conformational change, which is essential for virus-host fusion  is the most conserved amongst the flavivirus proteins, and is essential for viral RNA synthesis. Since host cells lack these enzymes, the specificity makes them one of the most promising and intensively studied classes of antiviral targets. RdRp can be targeted by non-nucleoside inhibitors (NNIs) and nucleoside/nucleotide analog inhibitors (NIs)  as a methyl donor during viral cap formation  that catalyzes guanine N-7 and ribose 2′-in-vivo, manipulating a major metabolic pathway may have a more pleiotropic impact on cellular homeostasis  on host LDs, the interface of virus-host interactions with LDs and/or LD metabolism provides a rich source for potential antiviral interventions Table . First, Ideally, antiviral treatments should exert their effects as early as possible after infection. This is particularly true for acute flaviviral infections such as DENV. Targeting intracellular host factors, however, is perhaps less effective in preventing the onset of an infection compared to other inhibitors, which block viral entry. The advantages and disadvantages of antiviral strategies against HCV and flaviviruses by targeting viral components and host factors including those involved in LD metabolism are summarized in Table Flaviviridae family often cause perturbations in cellular energy and lipid homeostasis during infection. This has been reported for DENV, WNV, and HCV infection. Therefore, targeting cellular LDs offers possibilities for such interventions, including inhibition of lipid metabolism and disruption of interactions with viral components. Although knowledge on the participation of LDs during infection of HCV and flaviviruses has significantly progressed, comparative studies that aim to determine the shared or specific requirements of LD components for these pathogens are still lacking. In addition, much of the information available is from in-vitro studies, while the in-vivo relevance remains unexplored. Therefore, a more comprehensive understanding of the molecular biology of viruses and their dependence on host LD metabolism is of utmost priority for development of broad-spectrum and specific anti-flaviviral strategies.Despite being an immense global health problem, there are no affordable and efficient prophylactic or therapeutic treatments for some pathogenic flaviviruses. It is imperative to have alternative therapeutic strategies of inhibiting specific steps in the intracellular virus life cycle to combat infection. Viruses from the JZ and YL drafted the manuscript and contributed equally to this work. SS supervised, evaluated, and edited the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Following neuro- and gliogenesis, nestin is replaced by cell type-specific intermediate filaments, e.g., neurofilaments for panneuronal expression and glial fibrillary acidic protein as a specific marker of mature astrocytes. While previous work have been mostly focused on the neuronal fate of nestin-positive progenitors, in the present study, we sought to investigate in To visualize effects of neuroinflammation on neurogenesis/gliogenesis, we created a transgenic model bearing the dual reporter system luciferase and GFP under transcriptional control of the murine nestin promoter. In this model, transcriptional activation of nestin was visualized from the brains of living animals using biophotonic/bioluminescence molecular imaging and a high resolution charged coupled device camera. Nestin induction profiles in vivo and in tissue sections were analyzed in two different experimental paradigms: middle cerebral artery occlusion and lipopolysaccharide-induced innate immune stimuli.We report here a context- and injury-dependent induction and cellular expression profile of nestin. While in the baseline conditions the nestin signal and/or GFP expression was restricted to neuronal progenitors, the cellular expression patterns of nestin following innate immune challenge and after stroke markedly differed shifting the cellular expression patterns towards activated microglia/macrophages and astrocytes.Our results suggest that nestin may serve as a context-dependent biomarker of inflammatory response in glial cells including activated microglia/macrophages.The online version of this article (doi:10.1186/s12974-017-0816-7) contains supplementary material, which is available to authorized users. Nestin is a class IV intermediate filament  highly ereal time how nestin signals and its cellular expression patterns are controlled in the context of neuroinflammatory, innate immune challenge and ischemic brain injury. To visualize the nestin signal from the brains of living mice, we created a transgenic model co-expressing reporter genes luciferase (luc) and green fluorescent protein (GFP) under transcriptional control of the murine nestin gene promoter. The advantage of the dual reporter system emerged from the fact that fluorescence signals can be used to achieve microscopic resolution and detection of the GFP signals from the specific cell subtypes, while bioluminescence, owing to favorable emission spectra of luciferase (above 620 nm), is optimized for live whole animal imaging  under the transcriptional control of the nestin gene promoter. The 5.1-kb fragment of the nestin gene promoter was amplified from the recombinant plasmid pNERV and cloned into a TOPO vector then sequenced and inserted into the recombinant plasmid pIRES-Luc2-AcGFP Fig. . The feaene Fig. . To deteIn the adult brain, neurogenesis persists in two brain regions referred to as neurogenic niches, the subgranular zone of the dentate gyrus (DG) in the hippocampus and the subependyma of the lateral ventricles called the subventricular zone (SVZ). While SVZ progenitors give rise to rostral migratory stream and incorporate into the olfactory bulb as new olfactory neurons , the subTo date, it has been widely established that ischemic injury in the brain triggers adult neurogenesis in the SVZ of the lateral ventricles and the SGZ of the dentate gyrus –21. FurtPrevious evidence suggests that the nestin-positive progenitors may also give rise and differentiate into GFAP-positive astrocytes; we next investigated the cellular expression/induction patterns of nestin after stroke. Based on the results obtained by in vivo imaging, i.e., peak signal induction of nestin see Fig. , the iscContrary to brain response to injuries, including stroke, previous evidence suggests that the acute and chronic inflammation may have a negative impact on neurogenesis –27. To aWhile nestin have been widely considered as a putative neuronal stem cell marker, in neuroinflammatory and in post-injury conditions, nestin could also be observed in activated and GFAP-positive astrocytes (see Figs. One of the important features of microglial activation, especially in the context of ischemic injury, is a robust proliferative response , 32. ThuTaken together, our results strongly suggest that following injuries and in the context of acute innate immune challenge, in addition to reactive astrocytes, activated Iba-1 microglia/macrophages strongly up-regulate nestin. This suggests that nestin may serve as a context-dependent marker of activated microglia/macrophages.Nestin, a class VI intermediate filament, is a well-established putative neuronal stem cell marker. Here we describe the nestin-luc/GFP reporter mouse model as a novel transgenic tool for real-time analysis and/or visualization of the nestin signals from the brains of living animals. Using in vivo biophotonic/bioluminescence imaging, we were able to visualize the baseline levels, as well as the spatial and temporal dynamics of the nestin biophotonic signal induction following ischemic injury and in the experimental paradigms of the acute and chronic neuroinflammation. Here it is important to mention that in all experimental paradigms, analysis of the fluorescence GFP transgene signal at the cellular level revealed a co-expression between endogenous nestin and the nestin-driven GFP transgene. This suggests that nestin-luc/GFP reporter mouse represents a valid model system for real-time analysis of nestin induction and/or expression patterns. By combining in vivo bioluminescence/biophotonic imaging with double immunofluorescence, we report here that in baseline, physiological conditions, in the adult brain, nestin expression is indeed restricted to neuronal progenitor cells. Thus, the obtained in vivo biophotonic signal can be used to assess neurogenic activity from the brains of adult mice. Importantly, ischemic brain injury as well as controlled innate immune challenge induced significant increase of the nestin signal in vivo. Contrary to physiological conditions where the GFP signal co-localized perfectly with nestin-positive progenitors, the double-immunofluorescence analysis of the nestin-driven transgene gfp revealed, however, that in neuroinflammatory conditions, the cellular expression and/or induction of the nestin biophotonic signal was not restricted to neuronal progenitors. As expected, we observed a marked increase in nestin expression/induction in the GFAP-positive reactive astrocytes. However, to our surprise, following LPS challenge as well as after MCAO, we observed a significant increase in the nestin expression in activated Iba-1 microglia/macrophages (see Figs. Brain injuries and neurodegenerative disorders are associated with acute and chronic brain inflammation. The relationship between brain inflammation and the regulation of neurogenesis has been well documented and remains the subject of intense investigation. Notably, recent collective evidence indicates that neurogenesis is affected during brain injury and in distinct neuroinflammatory conditions by the dysregulation of cytokines, chemokines, neurotransmitters, and reactive oxygen species caused by inflammation and mediated by activated macrophages, microglia, and reactive astrocytes –42. MultA novel transgenic tool that we generated in our laboratory allowed us to investigate the role and/or spatial and temporal dynamics of the nestin expressing cells in brain response to injury and in neuroinflammatory conditions. For example, a great advantage of our in vivo model system is that it allowed us to track how nestin expressing cells are responding to different types of neuroinflammatory conditions directly from the brains of intact animals (see Figs. In summary, our results suggest that neuroinflammatory conditions such as brain ischemia and innate immune challenge strongly up-regulate nestin signals in the brain of living animals. Interestingly, while in physiological conditions, and in the adult brain, nestin expression is restricted to NPGs in their respective niches and the neuroinflammatory conditions are associated with marked induction of nestin in astrocytes as well as in activated microglia/macrophages. Based on our results, we propose that nestin may serve as a context-dependent biomarker of inflammatory response in glial cells including activated brain microglia/macrophages.


Expanding access to medication abortion through pharmacies is a promising avenue to reach women with safe and convenient care, yet no pharmacy provision interventions have been evaluated. This observational non-inferiority study investigated the effectiveness and safety of mifepristone-misoprostol medication abortion provided at pharmacies, compared to government-certified public health facilities, by trained auxiliary nurse-midwives in Nepal.Auxiliary nurse-midwives were trained to provide medication abortion through twelve pharmacies and public facilities as part of a demonstration project in two districts. Eligible women were ≤63 days pregnant, aged 16–45, and had no medical contraindications. Between 2014–2015, participants (n = 605) obtained 200 mg mifepristone orally and 800 μg misoprostol sublingually or intravaginally 24 hours later, and followed-up 14–21 days later. The primary outcome was complete abortion without manual vacuum aspiration; the secondary outcome was complication requiring treatment. We assessed risk differences by facility type with multivariable logistic mixed-effects regression.Over 99% of enrolled women completed follow-up (n = 600). Complete abortions occurred in 588 (98·0%) cases, with ten incomplete abortions and two continuing pregnancies. 293/297 (98·7%) pharmacy participants and 295/303 (97·4%) public facility participants had complete abortions, with an adjusted risk difference falling within the pre-specified 5 percentage-point non-inferiority margin . No serious adverse events occurred. Five (1.7%) pharmacy and two (0.7%) public facility participants experienced a complication warranting treatment .Early mifepristone-misoprostol abortion was as effective and safe when provided by trained auxiliary nurse-midwives at pharmacies as at government-certified health facilities. Findings support policy expanding provision through registered pharmacies by trained auxiliary nurse-midwives to improve access to safe care. Unsafe abortion contributes substantially to maternal mortality and morbidity worldwide, accounting for approximately 18% of maternal deaths . Unsafe Efforts to improve access to safe abortion have focused on expanding the provider base, as well as decentralizing medication abortion (MA) provision beyond traditional hospital and clinic settings. On the World Health Organization (WHO) Essential Medicines List for developing countries , mifepriExpanding access to MAB through regulated pharmacies may also be a promising avenue to reach women with safe care, though no interventions have been evaluated . In manyNepal is a leader in innovating access to abortion. Since abortion was decriminalized in Nepal in 2002 , access In this observational demonstration study, we tested the hypothesis that the effectiveness and safety of mifepristone medication abortion provided by trained ANMs through pharmacies would not be inferior to provision through public health facilities that are government-certified to provide MAB. Empirical data on the effectiveness and safety of MAB provision from pharmacies by trained providers do not yet exist but are essential to inform evidence-based policy in Nepal and elsewhere.This study was an observational, non-inferiority study comparing outcomes of medication abortion provided by trained auxiliary nurse-midwives in two settings: pharmacies and government-certified public health facilities. Sites were located in both semi-urban and remote regions of the Chitwan and Jhapa districts in the lower Terai region, bordering India. Twelve sites participated: six privately-owned pharmacies and six public health facilities, including four primary health care centers and two health posts. Primary health care centers provide basic health care services, minor surgeries, and aspiration and medication abortion; they are typically staffed by a physician, a few nurses/ANMs, and non-clinical staff. Health posts provide basic health care services and are staffed by a nurse/ANM, a health worker, and non-clinical staff; some are approved to provide medication abortion. Participating pharmacies had to be registered with the Department of Drug Administration, Ministry of Health and Population; have locked storage for data; and have a private space for patient examination, a typical set-up in Nepal .Clinical study procedures were conducted by six ANMs. Each was trained as a skilled birth attendant, had required government training and certification to provide MAB at a public facility, and worked in a pharmacy. MAB outcomes can vary substantially between providers based on experience and tendency to intervene . BecauseANMs completed a three-day training on study procedures, ethics and voluntary informed consent, and provision of MAB through the pharmacy, including ensuring confidentiality, storage of clinical case reports, and referrals. At training completion, each participating pharmacy received certification from the Ministry of Health and Population to provide MAB for the experimental demonstration study period. One ANM was relocated during the study; a replacement was trained on-site by a study investigator. Six female research assistants with nursing training were selected and trained to conduct non-clinical data collection.Women presenting at study sites seeking medication abortion were eligible to participate if they were aged 16–45 and had an established pregnancy of ≤63 days based on pelvic exam performed at the site. Women were excluded if they had already attempted abortion with the same pregnancy, lived outside of Nepal, had any medical contraindications to mifepristone-misoprostol, or were unable to provide consent or complete study visits.Data were collected October 2014-September 2015. A pilot phase among 57 participants was conducted October-December 2014 to assess feasibility and test instruments. Results of an interim analysis were shared with two University of California, San Francisco (UCSF) obstetrician-gynecologists to determine that complications or incomplete abortions at pharmacy sites were not higher than expected. As pre-specified in the protocol, because no changes to the protocol were required, pilot data were included in analyses.Ethical approval was obtained from the UCSF Committee on Human Research and the Nepal Health Research Council. The study was endorsed by the Family Health Division, Ministry of Health and Population, Nepal. We followed published guidelines for reporting of non-inferiority trials .For women presenting at all study sites requesting medication abortion, ANMs completed clinical screening for MAB eligibility, as is standard patient care. ANMs recorded last menstrual period and MAB contraindications. They conducted a pelvic exam to assess gestational length and identify signs of ectopic or adnexal mass or infection. Women meeting MAB eligibility criteria (both those enrolling and not enrolling) received MAB counseling, services, and information on when and where to seek care for complications.Clinical procedures at all sites followed the standard Nepali medication abortion protocol , which iWomen meeting eligibility criteria provided verbal informed consent. After taking mifepristone, participants completed interviewer-administered baseline questionnaires assessing sociodemographics, pregnancy and contraceptive history, pregnancy intentions, and experiences seeking services.In the Nepali protocol, patients are provided context-appropriate instructions for when to seek care for a complication or incomplete abortion; follow-up visits are not mandatory . HoweverData were managed by the Center for Research on Environment Health & Population (CREHPA). Research assistants secured data collection instruments at the study sites. Instruments were transferred to the CREHPA offices monthly.The primary outcome was successful complete abortion (versus incomplete abortion or continuing pregnancy), without aspiration abortion, within 30 days of mifepristone . IncomplThe secondary outcome was experience of complications requiring treatment, including any case in which participants sought treatment or ANMs provided or referred for care at a follow-up visit. Serious adverse events, including hemorrhage needing blood transfusion and conditions requiring hospitalization, were captured. Finally, we assessed side effects experienced and satisfaction with services and MAB itself. Data for all outcomes were recorded on follow-up clinical case reports and questionnaires.Lancet study of midlevel provider MAB provision ; complication aRD = 1.7% .Acceptability of services was high across sites, with no differences by study arm . SatisfaIn this observational non-inferiority study, the effectiveness and safety of early mifepristone-misoprostol medication abortion provided by auxiliary nurse-midwives at pharmacies was as effective and safe as compared to when provided by ANMs at government-certified health facilities. Our study showed ANM provision of MAB in both pharmacies 98.7%) and public facilities (97.4%) was as effective as has been demonstrated in other studies using the same regimen (91–99%) [% and pubWhile nurse and ANM provision expands the abortion provider base, the potential of this trained workforce to reach women is limited by the requirement that services be provided from government-certified public health facilities. Pharmacies are more accessible than clinics, particularly in rural and mountainous areas, and are often the first contact point for women seeking services . The levThis study has limitations. Public health facility participants returning to the facility for care may have been more likely to receive intervention due to the presence of other clinicians, thereby biasing results in favor of pharmacies; however, incomplete abortions and complications were infrequent in both facility settings in this study. The 14–21 day follow-up period might not have detected delayed complications or ongoing pregnancies. However, study ANM remained in touch with participants until any issues detected were fully resolved, and it is reasonable to believe that most participants who experienced a delayed complication would return to the study facility for care. Our measures of satisfaction did not capture the acceptability of specific aspects of care provided. Finally, given feasibility constraints for a government-approved demonstration project, we were limited to including twelve recruitment sites and six ANMs. We had planned originally for pharmacy providers to rely on self-reported date of last menstrual period for assessment of gestation. Study ANMs, however, were uncomfortable omitting the pelvic exam because they were accustomed to conducting it. Our findings are thus not generalizable to pharmacies without clinical exam space, nor do they apply to unregulated pharmacies or those without ANMs with abortion training. Research should examine whether removing the pelvic exam from the baseline clinical assessment affects abortion effectiveness and safety.This study is the first to our knowledge to evaluate with a rigorous design and control group the effectiveness of medication abortion provision by trained clinicians in pharmacy settings. Our design isolated the effects of facility environment from the qualifications of providers on medication abortion outcomes. We had high (>99%) follow-up, supporting the internal validity of results. Importantly, this research with ANMs was clinically and ethnically appropriate, conducted in a manner consistent with World Health Organization guidelines, the scientific literature on ANM provision of abortion care, and current clinical practice and law in Nepal. Specifically, the safety and effectiveness of MAB when provided by non-physician clinicians, including nurses and ANMs, has been firmly established in peer-reviewed research –11. The Despite improvements in access to safe abortion care in Nepal, women continue to face obstacles to safe abortion and to seek care from unskilled providers, with access to safe care particularly constrained in rural regions . This st


Intra-abdominal infections (IAIs) are common surgical emergencies and have been reported as major contributors to non-trauma deaths in the emergency departments worldwide.The cornerstones of effective treatment of IAIs are early recognition, adequate source control, and appropriate antimicrobial therapy. Prompt resuscitation of patients with ongoing sepsis is of utmost important.In hospitals worldwide, non-acceptance of, or lack of access to, accessible evidence-based practices and guidelines result in overall poorer outcome of patients suffering IAIs.The aim of this paper is to promote global standards of care in IAIs and update the 2013 WSES guidelines for management of intra-abdominal infections. The world’s burden of emergency surgery diseases is significant and appears to be increasing. Emergency services and acute surgical care constitute a major gap in the focus of the health sector worldwide, and several issues need to be addressed in order to promote a global dialogue on what is the most appropriate way to configure acute care surgery worldwide . AlthougComplicated intra-abdominal infections (cIAIs) are an important cause of morbidity and mortality, particularly if poorly managed. A recent multi-center observational study, conducted in 132 medical institutions worldwide during a 4-month period (October 2014–February 2015) enrolled 4553 patients with cIAIs [The aim of these guidelines is to present an evidence-based international consensus position on the management of IAIs, from collaboration of a panel of experts, with a view to promoting the standards of care for the management of IAIs worldwide.These guidelines have been formulated by international collaboration and discussion among an expert panel of clinicians, practicing in the field of emergency surgery. These consensus guidelines have been facilitated and coordinated by the board of the World Society of Emergency Surgery and are an update of the 2013 WSES guidelines on this topic.The statements are formulated and graded according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) hierarchy of evidence from Guyatt and colleagues , summariThe key factors in the effective treatment of cIAIs are (a) a prompt diagnosis, (b) adequate resuscitation, (c) early initiation of appropriate antibiotic therapy, (d) early and effective source control, and finally, (e) reassessment of the clinical response and appropriate adjustment of the management strategy.Abdominal sepsis represents the host’s systemic inflammatory response to intra-abdominal infections. Sepsis is a dynamic process that can evolve into conditions of varying severity , 11. TheThird International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) has recently been published  and updaSome concerns about the new definition of sepsis have been reported .Since the first classification in 1991 , the defDocumenting the burden of critical illness in low-resource settings is challenging. In these settings, a robust triage system that quickly recognizes critically ill patients and transfers them immediately to an acute care unit are a vital component of the emergency services .Moreover in many areas worldwide, there are limited resources for intensive investigations, as a consequence, any process of improving quality of sepsis care globally should focus on simple diagnostic criteria based on physical examination findings that can recognize patients needing critical care. In these settings, a feasible, low-cost method of rapidly identifying patients requiring critical care should be crucial.2, which would require an arterial blood gas measurement.Sepsis-3 definition introduces Quick SOFA (qSOFA) as a tool for identifying patients at risk of sepsis with a higher risk of hospital death both inside and outside critical care units. However, qSOFA does not define sepsis and the new sepsis definitions recommend using an increase in the SOFA score of two points or more to represent organ dysfunction. The SOFA score is potentially not accessible everywhere, especially for PaOEarly warning scores utilize physiological, easy-to-measure parameters, assessing physiological parameters such as systolic blood pressure, pulse rate, respiratory rate, temperature, oxygen saturations, and level of consciousness .In patients with intra-abdominal infections, early warning scores associated with abdominal signs and symptoms such as abdominal pain and abdominal rigidity can screen patients needing immediate acute care surgery.Finally, although some patients with ongoing sepsis may not have elevated lactate levels at presentation or during their clinical course , 25, lacEarly recognition of the patient with ongoing abdominal sepsis is an essential step for an effective treatment.Prompt administration of intravenous fluids for resuscitation is critical in patients with an ongoing sepsis. This initial resuscitation should be titrated to the clinical response, and not solely guided by a predetermined protocol. Vasopressor agents may serve to augment and assist fluid resuscitation, particularly where this therapy alone is failing (Recommendation 1A).The data from WISS study showed that mortality was significantly affected by sepsis––mortality by sepsis status was no sepsis 1.2%, sepsis only 4.4%, severe sepsis 27.8%, and septic shock 67.8% [Identifying patients with ongoing sepsis early and correcting the underlying microvascular dysfunction may improve patient outcomes. If not corrected, microvascular dysfunction can lead to global tissue hypoxia, direct tissue damage, and ultimately, organ failure .Fluid therapy to improve microvascular blood flow and increase cardiac output is an essential part of the treatment of patients with sepsis. Crystalloid solutions should be the first choice because they are well tolerated and cheap . They shThe Surviving Sepsis Campaign (SSC) is a joint collaboration of the Society of Critical Care Medicine and the European Society of Intensive Care Medicine committed to reducing mortality from severe sepsis and septic shock worldwide in 2002. In 2012, the SSC updated its guidelines. SSC guidelines have been regarded as the standard of care in patients with severe sepsis and septic shock in many hospitals worldwide . HoweverThe 2016 Surviving Sepsis Campaign International Guidelines for Management of Sepsis and Septic Shock was recently published . PreviouThese data indicate that an early identification and prompt administration of intravenous fluids are mandatory. However, initial resuscitation should no longer be based on a predetermined protocol but on clinical endpoints.Hypotension is the most common indicator of inadequate perfusion. The SSC advocated a mean arterial pressure (MAP) goal of 65 mm Hg during the first 6 h of treatment. It was confirmed by a randomized controlled trial “Sepsis and Mean Arterial Pressure” (SEPSISPAM) examining high versus low MAP goals in patients with septic shock. It demonstrated that targeting a mean arterial pressure of 80–85 mm Hg, as compared with 65–70 mm Hg, in patients with septic shock undergoing resuscitation did not result in significant differences in mortality at either 28 or 90 days .Particularly in patients with abdominal sepsis, requiring urgent surgical intervention, overly aggressive fluid resuscitation may increase intra-abdominal pressure and worsen the inflammatory response, which is associated with a high risk of complications , 40. In Vasopressor agents should be administered to restore organ perfusion if fluid resuscitation fails optimizing blood flow and if hypotension persists following fluid loading. These agents should be globally available. Vasopressor and inotropic agents have increasingly become a therapeutic cornerstone for the management of sepsis. They have excitatory and inhibitory actions on the heart and vascular smooth muscle, as well as important metabolic, central nervous system, and presynaptic autonomic nervous system effects. The optimal timing of vasopressors relative to fluid infusion has been debated. Recently, a large multi-center retrospective analysis of 2849 patients with septic shock, investigators found that mortality was lowest when vasopressors were delayed by 1 h and infused from hours 1 to 6 following onset of shock . Norepin2). It has been suggested to be administered to pre-existing vasopressor therapy in the presence of myocardial dysfunction, defined as elevated cardiac filling pressures and low cardiac output. However, dobutamine increases DO2 to supranormal values and in critically ill patients, it has raised serious questions regarding its safety in the treatment of septic shock. Because dobutamine provides direct stimulation of the β-1 adrenergic receptors, it is recognized as more problematic with regard to tachycardia and arrhythmia.Dobutamine is an inotropic agent used to treat septic shock patients increasing cardiac output, stroke index, and oxygen delivery .The diagnosis of intra-abdominal infections is based primarily on clinical assessment. Typically, the patient is admitted to the emergency department with abdominal pain and a systemic inflammatory response, including fever, tachycardia, and tachypnoea. Abdominal rigidity suggests the presence of peritonitis. Hypotension and hypoperfusion signs such as lactic acidosis, oliguria, and acute alteration of mental status are indicative of ongoing sepsis.In many countries worldwide, a large proportion of patients with diffuse peritonitis still present to the hospital with unacceptable delay. This event reduces the percentage of surviving at the lowest rates in the world . In emerIn rural areas of LMICs with limited access to surgical care and CT, plain X-ray abdomen and ultrasound can help to identify and diagnose surgical emergencies cost-effectively, allowing efficient use of resources , 46.CT may be very useful especially when the diagnosis is uncertain. In high-income countries, it has become the gold standard. In 2006, a meta-analysis by Doria et al. demonstrated that CT imaging featured significantly higher sensitivity and resolution than ultrasound in studies of both children and adults with acute appendicitis .Proposals of staged algorithmics with a step-up approach with CT performed after an inconclusive or negative US were proposed in the setting of acute appendicitis and acute diverticulitis –51.The timing and adequacy of source control are important in the management of intra-abdominal infections; late and/or incomplete procedures may have severely adverse consequences on outcome especially in critically ill patients.IAIs include several different pathological conditions and are usually classified into uncomplicated and complicated . In uncoPeritonitis is classified into primary, secondary, or tertiary peritonitis . PrimaryAs a general principle, the most established source of infection should be totally controlled as soon as possible. However, source control requires general anaesthesia that may not be readily available in some areas of the world. In many rural areas, patients must be centralized to urban centers with the loss of much time, largely due to transport delays. Furthermore, the urgency of intervention is also affected by the rapidity of the evolution of clinical symptoms.Source control encompasses all measures undertaken to eliminate the source of infection, reduce the bacterial inoculum, and correct or control anatomic derangements to restore normal physiologic function , 56. TheIn recent years, laparoscopy has been gaining wider acceptance in the diagnosis and treatment of intra-abdominal infections. The laparoscopic approach in the treatment of peritonitis is feasible for many emergency conditions. It has the advantage to allow, at the same time, an adequate diagnosis and appropriate treatment with a less invasive abdominal approach . HoweverEtiological factors of peritonitis show a wide geographical variation and different spectrum in the various regions of the world. Table p < 0.001) as well as a more advanced disease profile associated with perforation and severe intra-abdominal sepsis .Acute appendicitis is both the most common general surgery emergency presentation, as well as the most common cause of intra-abdominal sepsis, worldwide. The WISS study  confirmeThe natural history of appendicitis has been described in three stages: (1) a normal appendix, (2) uncomplicated acute appendicitis, and (3) complicated appendicitis, according to their macroscopic and microscopic appearance and clinical relevance . The higUnfortunately, the clinical presentation of appendicitis is often inconsistent. While the clinical diagnosis may be clear in patients presenting with classic signs and symptoms, atypical presentations may result in delay in treatment. Therefore, diagnostic scoring systems have been described with the aim to provide clinical probabilities that a patient has acute appendicitis. The development of these scores may contribute to diagnosis and by easily applicable clinical criteria and simple laboratory tests a score which classifies the probability of diagnosis may be attributed to the patient. In 1986, Alvarado published his own method for the early diagnosis of acute appendicitis . A scoreRecently, WSES guidelines for diagnosis and treatment of acute appendicitis were published Appendectomy remains the treatment of choice also for acute appendicitis. Antibiotic therapy is a safe means of primary treatment for patients with uncomplicated acute appendicitis, but it is less effective in the long-term due to significant recurrence rates and probably needs the certainty of a CT proven diagnosis of uncomplicated appendicitis (Recommendation 1A).Antibiotics alone may be useful to treat patients with early, non-perforated appendicitis, even if there is a risk of recurrence , 72. In Both open and laparoscopic appendectomies are viable approaches to surgical treatment of acute appendicitis (Recommendation 1A).The advent of laparoscopy has modified the surgical treatment of acute appendicitis in high-income countries. In contrast, in many areas of the world, the challenges posed by the burden of primary healthcare concerns have limited support for development of modern tertiary healthcare facilities, and laparoscopic surgery is practiced in only a few tertiary hospitals. In the last years, several prospective randomized studies, meta-analyses, and systematic critical reviews have been published on the topics of laparoscopic appendectomy. Laparoscopic appendectomy is safe and effective, but open surgery still confers benefits, in particular with regard to the likelihood of postoperative intra-abdominal abscess. In a meta-analysis by Li et al.  includinPatients with a periappendiceal abscess can be managed with percutaneous image-guided drainage in surgical departments with ready access to diagnostic and interventional radiology. When percutaneous drainage is not available surgery is suggested (Recommendation 1B).In approximately 10% of patients, a periappendiceal abscess and inflammatory phlegmon is present at diagnosis. This is more frequently encountered in the situation of a delayed diagnosis. Clinical features of complicated appendicitis such as mass and abscess may include fever, tachycardia, palpation of mass, and extension of area of tenderness and rebound. Surgical management varies because a proportion of these cases will evolve into an ileocecal resection or a right-sided hemicolectomy if operated in the acute setting . In receIn patients treated conservatively, interval appendectomy may be not necessary following initial non-operative treatment of complicated appendicitis. However, interval appendectomies should always be performed for patients with recurrent symptoms (Recommendation 2B).Traditionally, an interval appendectomy has been offered to patients who initially underwent a non-operative approach to their appendiceal mass. However, the role of the interval appendectomy has been questioned, and controversy continues whether interval appendectomy is appropriate for adults with an appendiceal abscess. The main debate revolves around the recurrence rate, the complication rate of an interval appendectomy, and the potential for underlying malignancy. The results of a review by Andersonn and Petzold, based mainly on retrospective studies, supported the practice of non-surgical treatment without interval appendectomy in patients with appendiceal abscess or phlegmon . HoweverRoutine use of intraoperative irrigation for appendectomies does not prevent intra-abdominal abscess formation and may be avoided (Recommendation 2B).In 2011, a retrospective review of 176 consecutive appendectomies, open (39%) and laparoscopic (61%), at a university-affiliated tertiary care facility from July 2007 to November 2008 investigated routine use of intra-operative irrigation for appendectomies. The results did not show a decrease in postoperative intra-abdominal abscess with the use of intra-operative irrigation. Thirteen patients developed postoperative abscess: 11 with irrigation and two without irrigation. Ten of 13 patients who developed abscess were perforated; nine with irrigation and one without .Acute sigmoid diverticulitis is a common disease of the Western World and results in a significant number of hospital admissions. Data from Western populations suggest that up to one fifth of patients with acute diverticulitis are under the age of 50 years of age , 89. RecRecent WSES guidelines for the management of acute diverticulitis in the emergency setting were published .Clinical findings of patients having ALCD include acute pain or tenderness in the left lower quadrant, which may be associated with increased inflammatory markers including C-reactive protein (CRP) and white blood cell count (WBC). However, the clinical diagnosis of ALCD lacks accuracy: in a prospective analysis  conducteAntibiotics can be avoided in patients with CT findings of uncomplicated ALCD and without significant comorbid conditions or signs of sepsis. Patients should be clinically monitored to assess for resolution of the inflammatory processes (Recommendation 1A).ALCD is generally divided into uncomplicated and complicated. The utility of antimicrobial therapy in acute uncomplicated diverticulitis has been a point of controversy in the international medical community . In termOn the basis of clinical conditions, patients with diverticular smaller abscesses may be treated by antibiotics alone (Recommendation 1C).Patients with abscesses having a large diameter should be treated by percutaneous drainage and intravenous antibiotics (Recommendation 1C).Whenever percutaneous drainage of the abscess is not feasible or not available, based on the clinical conditions patients with large abscesses can be initially treated by antibiotic therapy alone. However careful clinical monitoring is mandatory (Recommendation 1C).Approximately 15–20% of patients admitted with ALCD have an abscess , and theA retrospective study assessing the effectiveness of antibiotics as sole initial therapy in patients with large diverticular abscess was published in 2015 by Elagili et al. . Thirty-p = 0.21). Patients treated with antibiotics had a significantly smaller abscess diameter . Postoperative complications in patients treated with antibiotics alone were significantly less severe than after percutaneous drainage based on the Clavien-Dindo classification (p = 0.04).Failure of initial treatment required urgent surgery in eight patients with persistent symptoms during treatment with antibiotics alone (25%) and in 21 patients (18%) after initial percutaneous drainage .Hartmann’s procedure has been considered the procedure of choice in patients with generalized peritonitis and remains a safe technique for emergency colectomy in diverticular peritonitis, especially in critically ill patients and in patients with multiple co-morbidities. However, restoration of bowel continuity after Hartmann’s procedure has been associated with significant morbidity . In receLaparoscopic peritoneal lavage and drainage may not be considered the treatment of choice in patients with diffuse peritonitis (Recommendation 1A).Recent investigation continues to define the role of laparoscopic peritoneal lavage in the treatment of ALCD, and unanswered questions remain. The latest prospective trials, including the SCANDIV, Ladies, and DILALA trials –111, havTreatments for perforated colonic carcinoma should both stabilize the emergency condition of the peritonitis and fulfil the technical objectives of oncological intervention (Recommendation 1B).Patients with perforated colonic carcinoma had a significantly poorer prognosis compared with patients with non-perforated colonic cancer. Colorectal cancer-induced perforation is considered an advanced stage disease due to the potential for peritoneal dissemination of tumor cells throughout the site of perforation , 113.The stage of illness, proximity of the perforation to the tumor, and the number of metastatic lymph nodes are positively correlated with reduced procedural- and cancer-free survival rates .Hartmann’s procedure has been widely accepted as an effective means of treating carcinoma of the left colon (with adequate R0 resection) in certain emergency scenarios .Patients presenting with diffuse peritonitis caused by colonoscopic perforation should undergo immediate surgical intervention, which typically involves primary repair or resection (Recommendation 1B).Recently, the frequency of colonic perforation has increased due to routinely performed advanced therapeutic endoscopy. The recent advent of endoscopic submucosal dissection (ESD) has resulted in a high incidence of perforation, although the indication for endoscopic therapy of colorectal neoplasm has been expanded.Over the last decade, many advancements have been streamlined to better address these perforations, yet there are no definitive guidelines for their optimal management .Endoscopic management is typically used to treat colonoscopy-associated perforations if they can be closed by endoscopic clipping during colonoscopy –119.Retrospective studies showed that conservative management of colonoscopic perforation could be an option for patients without overt symptoms of peritonitis or with a small defect size , 121.Early exploratory laparotomy with primary closure or bowel resection has been the standard treatment of colonoscopic perforation . In casep < .05).Iqbal et al. in a retrospective study  indicateAn early laparoscopic approach may be a safe and effective option for colonoscopy-related colonic perforation for experienced surgeons (Recommendation 2B).Laparoscopic surgery is a compromise that may minimize the risks of invasive surgery as well as those of insufficiently aggressive non-operative therapy –128.In the Zhang et al. study, their experience in laparoscopic direct suturing of colon perforations indicated that laparoscopic primary perforation repair was a safe and feasible repair method .If the area of perforation cannot be localized laparoscopically, the surgeon should begin with a laparotomy before proceeding further .Helicobacter pylori (H. pylori) and a diet high in salt. All these factors have in common that they affect acid secretion in the gastric mucosa [Gastroduodenal ulcer perforations have decreased in the last few years, largely due to the widespread adoption of medical therapies for peptic ulcer disease and decreasing incidence of helicobacter pylori infection in Western countries. However, ulcer disease is a still common emergency condition worldwide and is associated with mortality rates of up to 30% , 130. Thc mucosa . Stress Surgery is the treatment of choice for perforated peptic ulcers (Recommendation 1A).Simple closure with or without an omental patch is a safe and effective procedure to address small perforated ulcers (<2 cm) (Recommendation 1A).Surgery is the most effective means of source control in patients with PPU . The maiIn 2010, Lo et al. conducted a study to determine if an omental patch offers any clinical benefit that is not offered by simple closure alone . The stuScoring systems to predict disease severity or outcome in patients with gastroduodenal perforations are unreliable and not accurate and cannot be generalized from one population to another , 134.Laparoscopic repair of perforated peptic ulcers can be a safe and effective procedure for experienced surgeons (Recommendation 1A).Successful laparoscopic repair of perforated gastric and duodenal ulcers has been reported, though the technique has yet to be universally accepted. The literature was summarized in a recent systematic review . The autConservative treatment for PPU is seldom reported and restricted mostly to case reports and series, .Small bowel perforations are a less common source of peritonitis in the Western countries, compared with LMICs. In Western countries, most small intestinal perforations are due to unrecognized intestinal ischemia (mesenteric or strangulation) or inflammatory bowel disease such as Crohn disease. This pattern of disease is quite different to LMICs, where small bowel perforations are usually due to typhoid fever. Typhoid fever remains endemic in Asia, Africa, Latin America, the Caribbean, and Oceania . Ileal pSurgery is the treatment of choice for patients with small bowel perforations (Recommendation 1B).In the event of small perforations, primary repair is recommended (Recommendation 1B).There are many methods of surgical treatment of small bowel perforation, including primary closure, excision and closure, resection and primary anastomosis, limited right hemicolectomy, and stoma creation . PrimaryIn delayed cases with diffuse peritonitis, there can be severe inflammation and oedema of the bowel, resulting in friable tissue which precludes anastomosis, and therefore, an ileostomy should be performed as a life saving measure . LaparosClostridium difficile, Cytomegalovirus, and Histoplasmosis [Other infections that may rarely cause small bowel perforation in immuno-compromised patients include amoebic infection, lasmosis –150. RarTuberculosis (TB) remains prevalent worldwide. It is considered as a global health problem by the World Health Organization and is considered the most important communicable disease in the world.Although much of the burden is concentrated in high-burden settings in Asia and Africa, TB continues to be of concern in high-income nations. The number of tuberculosis cases has also been increasing in high-income countries, mainly because of immigration and as a consequence of acquired immunodeficiency syndrome (AIDS) and also because of the utilization of immunosuppressive drugs .Abdominal involvement in tuberculosis is the most common extra-pulmonary form of this infection.The most common site of extra pulmonary tuberculosis is the ileocecal region and terminal ileum .The clinical presentation of tuberculosis is variable and non-specific, with non-pathognomonic signs and symptoms. It may mimic other infectious or inflammatory pathological diseases, and even neoplastic conditions , 152.The most common complication of small bowel tuberculosis is obstruction due to the narrowing of the lumen by ileocecal tuberculosis or stricture of small intestine and perforation in ulcerative type of tuberculosis.In the case of abdominal tuberculosis perforation resection of the affected area and anastomosis may be the treatment of choice rather than primary closure (Recommendation 1C).Treatment of tubercular perforation of ileum depends upon the condition of the gut, general condition of the patient and number of perforations. The resection of the affected area and anastomosis may be the treatment of choice rather than primary closure .Cholelithiasis is a common disorder all over the world –155. ItsAcute cholecystitis develops in 1–3% of patients with symptomatic gallstones .In 2016, WSES guidelines for the management of acute calculous cholecystitis (AAC) were published .The diagnosis of acute cholecystitis is made on the basis of clinical features such as right upper quadrant pain, fever, and leukocytosis and is supported by findings from relevant imaging studies. Ultrasound is the investigation of choice in patients suspected of having acute cholecystitis . UltrasoEarly cholecystectomy is a safe treatment for acute cholecystitis and generally results in shorter recovery time and hospitalization compared to delayed cholecystectomies (Recommendation 1A).Several randomized controlled trials have investigated early laparoscopic cholecystectomy (ELC) versus delayed laparoscopic cholecystectomy (DLC) and meta-analysis –168. A rAmong patients with uncomplicated cholecystitis, if source control is complete, no postoperative antimicrobial therapy is necessary .Laparoscopic cholecystectomy is a safe and effective treatment for acute cholecystitis (Recommendation 1A).It is the first choice for patients with acute cholecystitis where adequate resources and skill are available. Some risk factors may predict the risk for conversion to open cholecystectomy.Multiple prospective trials have demonstrated that the laparoscopic cholecystectomy is a safe and effective treatment for acute cholecystitis –174. As In LMICs, laparoscopic surgery is just evolving in tertiary centers. Despite the low volume of patients and the absence of fluoroscopy in many hospitals results in treating acute cholecystitis seem to be comparable with high volume centers .Cholecystostomy is a safe and effective treatment for acute cholecystitis in critically ill and/or with multiple comorbidities and unfit for surgery patients (Recommendation 1B).Acute cholecystitis in elderly, critically ill patients still today remains a real challenge to treat. Despite the low rate of surgical impact from the laparoscopic approach, many patients are unfit for any surgery. In this subgroup of patients, urgent cholecystostomy with or without delayed laparoscopic cholecystectomy appears to be the correct clinical approach –198.Early diagnosis of gallbladder perforation and immediate surgical intervention may substantially decrease morbidity and mortality rates (Recommendation 1C).Gallbladder perforation is an unusual complication; occasionally, acute cholecystitis, inflammation, and fulminant infection may progress to ischemic necrosis and gallbladder perforation. Prompt surgical intervention is important in decreasing morbidity and mortality rates associated with this situation. The reported incidence of gallbladder perforation in acute cholecystitis is 2–11% –200, andThe gallbladder perforation is classified into three types: acute or type I-free perforation with generalized peritonitis, subacute or type II-pericholecystic abscess with localized peritonitis, and chronic or type III-cholecysto-enteric fistula . PerforaPerforation is rarely diagnosed pre-operatively. Delayed surgical intervention is associated with elevated morbidity and mortality rates, increased likelihood of ICU admission, and prolonged post-operative hospitalization –210.Acute cholangitis is an infectious disease characterized by acute inflammation and infection in the bile ducts resulting from a combination of biliary obstruction and bacterial growth in bile.Bacteria reach the biliary system either by ascent from the intestine or by the portal venous system . The mosThe key elements of therapy in acute cholangitis are adequate antimicrobial treatment to avoid or manage the septic complications and biliary decompression to restore biliary drainage in case of obstruction . The cliIn severe cholangitis, an early interventional approach is absolutely essential for survival.The type and timing of biliary drainage should be based on the severity of the clinical presentation, and the availability and feasibility of drainage techniques, such as endoscopic retrograde cholangiopancreatography (ERCP), percutaneous transhepatic cholangiography (PTC), and open surgical drainage.ERCP plays a central role in the management of biliary obstruction in patients with acute cholangitis.Endoscopic retrograde cholangiopancreatography (ERCP) is the treatment of choice for biliary decompression in patients with moderate/severe acute cholangitis (Recommendation 1A).n = 41) were significantly lower than those of T-tube drainage under laparotomy (n = 41). The authors concluded that morbidity and mortality of endoscopic naso-biliary drainage (ENBD) + endoscopic sphincterotomy are lower than those of T-tube drainage under laparotomy.A randomized controlled trial (RCT)  was condThere are various endoscopic transpapillary options available, including biliary stent or nasobiliary drain placement above the obstruction site ± sphincterotomy, all of which with their appropriate indications corresponding to disease severity and clinical context .Endoscopic biliary decompression by nasobiliary catheter or indwelling stent was equally effective for patients with acute suppurative cholangitis caused by bile duct stones in a prospective randomized trial published in 2002 . The indPercutaneous biliary drainage (PTBD) should be reserved for patients in whom ERCP fails (Recommendation 1B).There are patients in whom ERCP fails because of unsuccessful biliary cannulation, or an inaccessible papilla. In these cases, percutaneous biliary drainage (PTBD) is required. However, PTBD can lead to significant complications, including biliary peritonitis, hemobilia, pneumothorax, hematoma, liver abscesses, and patient discomfort related to the catheter .In 2012, a retrospective study comparing the safety and effectiveness of endoscopic and percutaneous transhepatic biliary drainage in the treatment of acute obstructive suppurative cholangitis was reported. It confirmed the clinical efficacy of endoscopic drainage as well as its ability to facilitate subsequent endoscopic or surgical intervention .Open drainage should only be used in patients for whom endoscopic or percutaneous trans-hepatic drainage is contraindicated or those in whom it has been unsuccessfully performed (Recommendation 2C).The indication for emergent open operation for acute cholangitis is rapidly disappearing. Emergency operation for severe cholangitis carries high mortality rates.Given the shortened length of hospitalization and the rarity of serious complications such as intra-peritoneal hemorrhage and biliary peritonitis, endoscopic drainage is preferred to open drainage –220.Post-operative peritonitis (PP) is a life-threatening hospital-acquired intra-abdominal infection with high rates of mortality , 222. ThOn the basis of the clinical conditions, the size of the abscess and the access to interventional radiology, antibiotics and/or percutaneous drainage may be suggested to treat post-operative localized intra-abdominal abscesses when there are no signs of generalized peritonitis (Recommendation 2C).Antibiotics and drainage may be the optimal means of treating post-operative localized intra-abdominal abscesses when there are no signs of generalized peritonitis. Several retrospective studies in the fields of surgery and radiology have documented the effectiveness of percutaneous drainage in the treatment of post-operative localized intra-abdominal abscesses .Prompt surgical source control should be performed following diagnosis of post-operative peritonitis. Ineffective control of the septic source is associated with significantly elevated mortality rates (Recommendation 1C).Complete surgical source control should be performed as soon as the patient has been maximally resuscitated. The inability to control the septic source is associated with an intolerably high patient mortality . Organ fIn 2009, a retrospective study by Chichom-Mefire et al.  analyzedPelvic inflammatory disease (PID) is an infection of the upper part of the female reproductive genital tract, including the uterus, fallopian tubes, and adjacent pelvic structures and may spread to the abdomen causing peritonitis , caused Neisseria gonorrhoeae and Chlamydia trachomatis are present in many cases; however, microorganisms including the endogenous vaginal and cervical flora may also cause PID. Genital tract mycoplasmas, most importantly Mycoplasma genitalium, have recently also been implicated as a cause of acute PID [The sexually transmitted cute PID . The glocute PID .Patients with tubo-ovarian abscess that does not respond to antibiotics should undergo surgical drainage (Recommendation 1C).Tubo-ovarian abscesses (TOA) may be a complication of PID. In women of reproductive age, TOA is one of the most common types of pelvic abscess. TOA are classically treated with broad-spectrum antibiotics. However, if antibiotic therapy is not sufficient, surgical drainage should be performed –235.Trauma continues to be a global major public health problem worldwide, and it is associated with high morbidity and mortality worldwide regardless of the socioeconomic status . Both blHollow visceral injury (HVI) has a more insidious presentation in this setting, often resulting in delayed diagnoses. Clinical signs may take time to develop, and imaging investigations are not completely sensitive. In addition, other injuries may distract the patient and clinical team, and accurate and timely diagnosis is often difficult. An improved outcome is reported in these settings, where, as a result of advances in imaging modalities, patient monitoring devices and prompt intervention is possible, while poor diagnostic facilities, late presentation, as well as late intervention adversely may affect the outcome in other settings , 239.Several mechanisms of bowel injury have been documented in the wake of blunt abdominal trauma. The most common injury is the posterior crushing of the bowel segment between the seat belt and vertebra or pelvis. It can result in local lacerations of the bowel wall, mural and mesenteric hematomas, transection of the bowel, localized devascularization, and full-thickness contusions. Devitalization of the areas of contusion may subsequently result in late perforation. Colonic injuries occurred less frequently than small intestinal injuries perhaps due to its location and the lack of redundancy, which prevents the formation of closed loops. Abdominal trauma may be associated with other additional co-morbid injuries, which could complicate the management and affect the outcome. Delay in diagnosis and treatment of the HVI may result in early peritonitis, hemodynamic instability and increased mortality and morbidity.Early surgical intervention is recommended in case of HVI (Recommendation 1C).Repair or anastomosis of intestinal injuries should be considered in all patients. A complete diversion of the faecal stream could be considered in colorectal injuries involving all layers in the setting of multiple injuries or comorbid conditions (Recommendation 1C).Early clinical recognition and surgical intervention is importance in case of HVI –241. TheDamage control laparotomy (DCL) in the context of HVI is accepted for small bowel injury in the context of coagulopathy, while colon ligation has been debated because of high complication rates and an increased incidence of leakage; however, delayed anastomosis of colon injuries after DCL may avoid stoma creation in some patients who are not candidates for anastomosis during initial intervention .Severe infection may be associated with marked inflammatory responses, which in the extreme circumstance may result in an excessive, dysfunctional immune response, with resultant physiological collapse. These shocked patients develop organ dysfunction and progress to a multiple organ dysfunction syndrome (MODS). In this case, a staged operative approach may minimize further physiological insults associated with a time and energy intense primary definitive operative strategy .Apart from a staged operative approach, the clinical team may also employ a planned re-laparotomy approach to re-examine pathology and facilitate repeated debridement of contaminated tissues. However, deciding if and when to perform a re-laparotomy in cases of secondary peritonitis remains difficult. Factors indicative of progressive or persistent organ failure during early post-operative follow-up analysis are the best indicators of ongoing infection . Three rThe on-demand re-laparotomy is recommended for patients with severe peritonitis because its ability to streamline healthcare resources, reduce overall medical costs, and prevent the need for further re-laparotomies (Recommendation 2A).In 2007, van Ruler et al. published a randomized, clinical study comparing planned and on-demand re-laparotomy strategies for patients with severe peritonitis . PatientThe open abdomen may be a viable option for treating physiologically deranged patients with ongoing sepsis, facilitating subsequent exploration and control of abdominal contents, and preventing abdominal compartment syndrome (Recommendation 1C).In order to define the role of OA with negative pressure therapy for improved biomediator clearance and mitigated systemic sepsis in patients with severe peritonitis a prospective trial is needed.The OA concept is closely linked to damage control surgery. In patients with ongoing sepsis, an OA approach may be required for controlling any persistent source of infection and preventing abdominal compartment syndrome.OA facilitates repeated abdominal exploration in the patients with severe peritonitis allowing easy second-look to control the source of infection and evacuate inflamed and toxic content, reducing the load of peritoneal cytokines and other inflammatory substances and preventing their production by removing the source itself .Temporary closure of the abdomen may be achieved by using gauze and large, impermeable, self-adhesive membrane dressings, both absorbable and non-absorbable meshes, and negative pressure therapy devices. The first and easiest method to perform a laparostomy was the application of a plastic silo (the “Bogota bag”). This system is inexpensive. However, it does not provide sufficient traction to the wound edges and allows the fascial edges to retract laterally, resulting in difficult fascial closure under significant tension, especially if the closure is delayed –247.At present, negative pressure techniques (NPT) have become the most extensively employed means of temporary closure of the abdominal wall.In 1986, Schein  et al. dRapid closure with the assistance of negative pressure therapy should be the primary objective in the management of patients with open abdomen, in order to prevent severe morbidity such as fistulae, loss of domain and massive incisional hernias (Recommendation 1B).Severe complications including loss of the abdominal domain, fistula formation, and the development of giant incisional hernias may be observed in this procedure. Following re-exploration, the goal should be the early and definitive closure of the abdomen, in order to reduce the complications associated with an open abdomen. Early definitive closure  is the basis of preventing or reducing the risk of complications –250.A systematic review and meta-analysis to evaluate whether early fascial abdominal closure had advantages over delayed approach was published in 2014 . The stuIf unable to close the abdomen early, a progressive closure device may be necessary.A systematic review and meta-analysis of the open abdomen and temporary abdominal closure techniques in non-trauma patients was recently published . The besJudicious use of antimicrobials is an integral part of good clinical practice. This attitude affects therapeutic efficacy of treatment and minimizes the risks associated with the selection of resistant pathogens.Antimicrobial resistance poses a global challenge. No single country can protect itself from the importation of resistant pathogens through travel and trade.The global nature of antimicrobial resistance calls for a global response, both in the geographic sense and across the whole range of sectors involved. Nobody is exempt from the problem .Although most surgeons are aware of the problem of antimicrobial resistance, most underestimate this problem in their own hospital. The necessity of formalized systematic approaches to the optimization of antibiotic therapy for patients with intra-abdominal infections in the setting of surgical units worldwide has become increasingly urgent.Knowledge of regional/local rates of resistance, when it is available, should be always an essential component of the clinical decision-making process when deciding the empirical treatment of infection (Recommendation 1C).Regional epidemiological data and resistance profiles are essential for selecting appropriate antibiotic therapy for IAIs , 255.However, while high-income countries (HICs) have extensive surveillance systems to monitor antimicrobial resistance , in low-The Study for Monitoring Antimicrobial Resistance Trends (SMART) provides the best available evidence for the current status of cIAIs worldwide. The SMART has monitored the in vitro susceptibility patterns of clinical gram-negative bacilli to antimicrobial agents collected worldwide from intra-abdominal infections since 2002 , 257. IsEscherichia coli causing intra-abdominal infections ranges from 60 to 93% in India, China, North America, Europe, and South Africa [Klebsiella pneumoniae isolates from urinary tract infections.In addition to the expected increased resistance to beta-lactams, fluoroquinolone resistance in ESBL-positive h Africa , 257. AlPredicting the pathogens and potential resistance patterns of a given infection begins by establishing whether the infection is community-acquired or healthcare-associated.or patients with community-acquired intra-abdominal infections (CA-IAIs), agents with a narrower spectrum of activity are preferred. However, in CA-IAI patients at risk for extended-spectrum beta-lactamases (ESBLs) producing Enterobacteriaceae infections, anti-ESBL-producer coverage may be warranted. For patients with healthcare-associated infections (HA-IAIs), antibiotic regimens with broader spectra of activity are preferred (Recommendation 1B).FEnterobacteriaceae, streptococci, and certain anaerobes (particularly Bacteroides fragilis) [Initial antibiotic therapy for IAIs is typically empirical in nature because a patient with abdominal sepsis needs immediate treatment, and microbiological data (culture and susceptibility results) can require up to 48–72 h before they are available for a more detailed analysis. Selection of appropriate empiric antibiotic therapy is critical for preventing unnecessary morbidity and mortality from cIAIs. The major pathogens involved in community-acquired intra-abdominal infections are usual residents of gastrointestinal flora, including ragilis) . Narroweragilis) .Enterobacteriaceae, which are prevalent in hospital-acquired infections but observed in CA-IAIs too [In the context of intra-abdominal infections, the main resistance problem is posed by ESBL-producing IAIs too .Enterobacteriaceae [Specific risk factors for ESBL-producing bacteria in community-acquired infections include recent exposure to antibiotics  within 90 days of IAI or known colonization with ESBL producing eriaceae .Enterobacteriaceae did not evolve with the same dynamics and large intra- and inter-regional variations have been observed. Poor access to drinking water, water pollution, and a high population density are efficient drivers for ESBL producing Enterobacteriaceae dissemination, as for any fecally-orally transmitted diseases [Although increasing overtime everywhere, carriage of ESBL producing diseases . Reportsdiseases , explaindiseases . In contdiseases .HA IAIs include hospital-acquired infections  but also infections in patients having recent hospitalization within 90 days, living in a skilled nursing or other long-term care facility, using aggressive medical therapies  at home and invasive therapies  in outpatient clinics within 30 days of the index infection.  HA-IAIs are commonly caused by more resistant flora. Here, complex multidrug regimens may be necessary for first line, empiric therapy. Although transmission of multidrug resistant organisms is most frequently documented in acute care facilities, all healthcare settings are affected by the emergence and transmission of antimicrobial-resistant microbes .Pseudomonas aeruginosa, very dangerous either in the abdominal cavity, [Acinetobacter spp, ESBL-producing K. pneumonia, E. coli and vancomycin-resistant enterococci (VRE) [Resistant flora may include the non-fermenting gram-negative  cavity,  or in he cavity, –265 and ci (VRE) , 267.K. pneumonia, are rapidly emerging as a major source of multidrug-resistant infections worldwide [P. aeruginosa, Stenotrophomonas maltophilia, and Acinetobacter baumannii) have exhibited alarming rates of increased resistance to a variety of antibiotics in health facilities worldwide. Both species are intrinsically resistant to several drugs and could acquire additional resistance to other important antimicrobial agents [P. aeruginosa coverage is only generally recommended for patients with HA-IAIs.During the last two decades, antimicrobial resistance has become a global threat to public health systems and some of the most common causes include erroneous use of antibiotics, and poor prevention and control with respect to infections. Particularly, infections caused by resistant gram-negative bacteria , 268 areorldwide –272 and l agents . P. aeruAmong gram-positive bacteria, enterococci play a significant role in IAI. Some studies have demonstrated poor outcomes among patients with documented enterococcal infections, particularly in those with post-operative IAI where enterococci coverage should be always considered , 274.The acquisition of glycopeptide resistance by enterococci has seriously affected the treatment and control of these organisms. Affected patients usually have multiple and relevant co-morbidities, with prolonged hospital stay and received long courses of broad-spectrum antibiotics .The burden of multidrug-resistant organism (MDRO) infections in LMICs is difficult to quantify because in these countries, routine microbiologic culture and sensitivity testing, especially in rural hospitals, are not performed because of the lack of personnel, equipment, and financial resources. As a consequence, antimicrobial therapy is empirical and a small collection of antimicrobials may be overused. This approach, although relatively inexpensive, may increase the emergence of antimicrobial resistance and hence sub-optimal clinical outcomes .Therefore, although resistance containment interventions in healthcare structures have mostly been implemented in high-income countries, there is a pressing need to intervene in the resistance pandemic also in LMIC.In the setting of HA-IAIs, post-operative peritonitis (PP) is a life-threatening hospital-acquired intra-abdominal infection with high rates of mortality and high risk for MDR infections and invasive candidiasis , 276. AnIn 2015, a retrospective review of patients with anastomotic leakage after colorectal cancer surgery , reporteIn critically ill patients antimicrobial therapy should be started as soon as possible.In these patients to ensure timely and effective administration of antibiotics, clinicians should always consider the pathophysiological status of the patient as well as the pharmacokinetic properties of the employed antibiotics (Recommendation 1B).An ineffective or otherwise inadequate antimicrobial regimen is one of the variables more strongly associated with unfavorable outcomes in critical ill patients .Empiric antimicrobial therapy should be started as soon as possible in patients with organ dysfunction and septic shock .However, apart from early timing of administration, selection of a pharmacological agent with penetration to the site of presumed infection, is necessary. Furthermore, the pathophysiological and immunological status of the patient and the pharmacokinetic properties of the chosen drugs warrant consideration. In the event of abdominal sepsis, clinicians must be aware that drug pharmacokinetics may be altered significantly in critically ill patients due to the pathophysiology of sepsis. For example, in critically ill patients, higher than standard loading doses of hydrophilic antimicrobials such as beta-lactams should be administered to ensure optimal exposure at the infection site independently of the patient’s renal function because of the dilution effect .Two patterns of bactericidal activity have been described for antibiotics: time-dependent activity  and concentration-dependent activity (where the efficacy is mainly related to the plasma peak concentration in relation to the MIC of the microorganism). The efficacy of time-dependent antibacterial agents in severely ill patients is related primarily to the maintenance of supra-inhibitory concentrations, and therefore, multiple daily dosing or continuous infusion may be appropriate , 281.On the other hand, some agents including aminoglycosides have concentration-dependent activity; therefore, for this antibiotic class, the entire daily dose should be administered in a once daily way (or with the lowest possible number of daily administrations) to achieve the highest peak plasma level and reduce the renal cortex exposure to aminoglycosides and reduces the risk of nephrotoxicity .In patients with uncomplicated IAI such as uncomplicated appendicitis and uncomplicated cholecystitis, where the source of infection is treated definitively, post-operative antibiotic therapy is not necessary (Recommendation 1A).In patients with complicated IAI undergoing an adequate source-control procedure, a short course of antibiotic therapy (3-5 d) is always recommended (Recommendation 1A).Patients who have ongoing signs of peritonitis or systemic illness (ongoing infection) beyond 5 to 7 days of antibiotic treatment, should warrant a diagnostic investigation (Recommendation 1C).Antibiotics should be used after a treatable infection has been recognized or if there is a high degree of suspicion of an infection. In the setting of uncomplicated acute IAIs such as uncomplicated appendicitis or cholecystitis, single doses have the same impact as multiple doses and post operative antimicrobial therapy is not necessary if source control is adequate , 283–285In the setting of cIAIs, a short course of antibiotic therapy (3–5 days) after adequate source control is a reasonable option , 283–285Patients who have ongoing signs of peritonitis or systemic illness beyond 5–7 days of antibiotic treatment normally warrant a diagnostic investigation to determine whether additional surgical intervention is necessary to address an ongoing uncontrolled source of infection or antimicrobial treatment failure. The prolonged and inappropriate use of antibiotics appears a key factor in the rapid rise of antimicrobial resistance worldwide over the past decade . A ratioThe choice of empiric antibiotic regimens in patients with IAI should be based on the clinical condition of the patients, the individual risk for infection by resistant pathogens, and the local resistance epidemiology (Recommendation 1C).Intra-abdominal infections may be managed with either single or multiple antibiotic regimens.P. seudomonas effect and anaerobic coverage, still make it an interesting option for management of severe IAIs. However, the use of piperacillin/tazobactam in patients with ESBLs infections is still controversial [Beta-lactam/beta-lactamase inhibitor combinations have an in vitro activity against gram-positive, gram-negative, and anaerobe organisms. Amoxicillin/clavulanate is still an option in mild community acquired IAIs. Broad-spectrum activity of piperacillin/tazobactam, including anti-oversial , 289, evP. aeruginosa. Cefepime, is a fourth-generation cephalosporin, with broader spectrum activity than third generation cephalosprins and effective against AmpC-producing organisms [Third generation cephalosporins including cefotaxime and ceftriaxone in association with metronidazole, may be still options for the treatment of mild IAIs. Ceftazidime and cefoperazone are third generation cephalosporins with an activity against rganisms . For emprganisms .Ciprofloxacin and levofloxacin are no longer appropriate choice as first-line treatment in many geographic regions because of the prevalence of fluoroquinolone resistance. However, when employed, these drugs should be used in association with metronidazole. In many current practices, the fluoroquinolones remain available for patients presenting allergy to beta-lactams, with mild intra-abdominal infections .P. aeruginosa and Enterococcus species. Group 2 includes imipenem/cilastatin, meropenem, and doripenem, which share activity against non-fermentative gram-negative bacilli [Carbapenems offer a wide spectrum of antimicrobial activity against gram-positive and gram-negative aerobic and anaerobic pathogens (with the exception of MDR-resistant gram-positive cocci). Group 1 carbapenems include ertapenem. This group has activity against extended-spectrum beta-lactamase (ESBL)-producing pathogens, but not active against  bacilli .Enterobacteriaceae. The recent and rapid spread K. pneumoniae carbapenems resistant has become a critical issue in hospitals worldwide. The use of carbapenems should be limited so as to preserve activity of this class of antibiotics because of the concern of emerging carbapenem-resistance [For more than two decades, carbapenems have been considered the agents of choice for multidrug-resistant infections caused by sistance .P. aeruginosa, but are ineffective against anaerobic bacteria and need association with metronidazole. Because of their toxic side effects, some guidelines did not recommend aminoglycosides for the routine empiric treatment of community-acquired IAI, reserving them for patients with allergies to beta-lactam agents or in combination with beta-lactams for treatment of IAI with suspected MDR gram-negative bacteria [Other options include aminoglycosides, particularly for suspected infections by gram-negative bacteria. They are effective against bacteria .Enterobacteriaceae, Acinetobacter species, and Stenotrophomonas maltophilia [P. aeruginosa or P. mirabilis. Caution is always advised for its use, in suspected bacteremia and healthcare-associated pneumonia [Tigecycline is a viable treatment option, especially in empiric therapy, for complicated IAIs due to its favorable in vitro activity against anaerobic organisms, enterococci, several ESBL- and in association carbapenemase-producing tophilia –295. It neumonia .The recent challenges of treating multidrug-resistant gram-negative infections, especially in critically ill patients, have renewed interest in the use of “old” antibiotics such as polymyxins and fosfomycin , 298, noEnterobacteriaceae and P. aeruginosa. These antimicrobials will be valuable for treating infections caused by MDR gram-negative bacteria in order to preserve carbapenems [P. aeruginosa [K. pneumoniae carbapenemase-producing bacteria [Ceftolozone/tazobactam and ceftazidime/avibactam are new antibiotics that have been approved for treatment of cIAIs (in combination with metronidazole) including infection by ESBLs producing bapenems . Ceftoloruginosa . Ceftazibacteria . Althougbacteria .In table Intra-operative cultures should be always performed in patients with HA-IAs or with CA- at risk for resistant pathogens or in critically ill patients. They allow expansion of the antimicrobial regimen if the initial choice is too narrow and to perform a de-escalation if the empirical regimen is too broad.When a microorganism is identified in clinical cultures, antimicrobial susceptibility testing (AST) should always be performed and reported to guide antibiotic therapy (Recommendation 1C).Although a lack of impact on patient outcomes by bacteriological cultures has been documented in patients with community-acquired IAI, especially in appendicitis , 303, thObtaining microbiological results from intra-operative culture from the site of infection has two advantages: (a) to expand antimicrobial regimen if the initial choice was too narrow and (b) to perform de-escalation of antimicrobial therapy if the empirical regimen was too broad .When a microorganism is identified in clinical cultures, antimicrobial susceptibility testing (AST) should always be performed to guide antimicrobial therapy. Data are reported in the form of MIC, which is the lowest concentration of an antibiotic that inhibits visible growth of a microorganism.The numerical MIC number, expressed as micrograms/ml, is usually reported by microbiology laboratories as a categorical guide for clinicians, i.e., as “susceptible”, “resistant”, or “intermediate,” according to Clinical or Laboratory Standards Institute (CLSI) criteria in the USA or the European Committee for Antimicrobial Susceptibility Testing (EUCAST) criteria in Europe.Knowledge of mechanisms of secretion of antibiotics into bile may be helpful in designing the optimal therapeutic regimen for patients with biliary-related intra-abdominal infections (Recommendation 1C).E. coli and K. pneumonia and anaerobes, especially B. fragilis [Organisms most often isolated in biliary infections are those isolated in intra-abdominal infections including the gram-negative aerobes, fragilis . The rolfragilis .Although there are no clinical data to support the use of antibiotics with biliary penetration for these patients, the efficacy of antibiotics in the treatment of biliary infections may depend on effective biliary antibiotic concentrations too . ObviousAntibiotics commonly used to treat biliary tract infections and their biliary penetration ability are illustrated in Table Empirical antifungal therapy for Candida species is recommended for patients with hospital-acquired IAIs, especially those with recent abdominal surgery or anastomotic leak (Recommendation 1C).Candida spp in the context of nosocomial peritonitis is incompletely defined. Its clinical presence is usually associated with poor prognosis. Empirical antifungal therapy for Candida spp is typically not recommended for patients with community-acquired intra-abdominal infections, with the notable exceptions of critically ill patients or immunocompromised patients  [Candida peritonitis [The epidemiological profile of ulators) . Recentlitonitis . IDSA guCandida species or who have no prior exposure to azoles [Preferred empiric therapy in critically ill patients or those previously exposed to an azole is an echinocandin . However, fluconazole, 600 mg (12 mg/kg) loading dose, then 400 mg (6 mg/kg) daily, should be still considered first-line antifungal therapy, in hemodynamically stable patients who are colonized with azole susceptible o azoles .IAIs remain an important cause of morbidity and mortality in modern surgical practice worldwide. The cornerstones of effective treatment of IAIs include early and accurate diagnosis, prompt resuscitation, early and effective source control, and initiation of appropriate antimicrobial therapy. IAIs have different disease and clinical spectra in the various regions of the world, and their etiological factors show a wide geographical variation. Promoting standards of care in the managing IAIs worldwide should be mandatory to grant management guidelines to all surgeons.In