Infections in Acute Pancreatitis: A Review

INTRODUCTION

Acute pancreatitis (AP) is a reversible inflammatory disease of the pancreas with acinar cell destruction¹ and characterized by pain in abdomen and increased pancreatic enzymes.² Acute pancreatitis is the most unpredictable disease of the digestive system and accounts for more than 50% of all hospital admissions for pancreatic diseases.³ The disease is generally mild and self-limiting. However, about 20% of the patients develop moderate to severe AP. Severe AP has poor prognosis because of infectious complications and leads to high morbidity, with mortality up to 35%.⁴ Globally, AP accounts for 1–60 deaths per 100,000 person-years, with an approximate mortality rate of 2–9%.^5,6 The reported incidence of AP varies from 12 to 38 per 100,000 population.^7,8 The indicators of infection include older age group, severity of pancreatitis, and earlier antibiotic use. Significant decrease in mortality can be possible with targeted therapy that can control systemic inflammation.

In recent years, the occurrence of AP has been notably rising,⁹ and because of its impending grave nature, particularly for severe AP, there is an increased claim on healthcare resources, as it requires several weeks to months for treatment. In this review, focus shall be made on various aspects of infections of AP, inclusive of diagnostic methods and commonly used management modalities.

PATHOGENESIS

Acute pancreatitis may appear as an interstitial disease or it may be complicated by pancreatic and/or peripancreatic necrosis, which may become infected in up to 40% of cases.¹⁰ The pathogenesis of secondary bacterial pancreatic infection is still under controversy. The pathogens can get into the pancreas through several routes such as the hematogenous route, through transmural colonic migration, or through the biliary system.¹¹ Acute pancreatitis is the setting for most infections of the pancreas, which can complicate various stages of pancreatitis. About 15–20% of patients develop moderately severe or more severe disease.¹² In a small group of patients, AP takes a serious course and develops into necrotizing pancreatitis that is characterized by localized or generalized pancreatic parenchymal necrosis and/or necrosis of the retroperitoneal peripancreatic fat. Patients who develop severe AP at an early stage have a high mortality rate.^13,14

Infected pancreatic necrosis (IPN) is an independent predictor of outcome in AP.^15,16 The mortality in AP ranges from 4% to 25%.^14,15,17 An important role is played by translocation of microorganisms across the intestinal wall and their virulence, and dysfunction of the lymphocytes. When the pancreatic necrosis becomes infected, mortality rate may go up to 30–32%.^16,18,19 There are two incidence peaks of mortality in AP.²⁰ The early phase or the first incidence peak occurs within the first week, when the immune system is enormously activated. This phase is associated with up to 50% of all deaths during the first 2 weeks of illness and mortality occurs due to multiple organ failure. In the late phase or the second incidence peak that can last for weeks to months, the mortality generally occurs due to sepsis.^21,22 The peak of the infection ranges from the 2nd to 4th week after the onset of pancreatitis.²³ The mean duration of infection is generally after 10 days of illness and peaks during the 2nd to 4th week after the onset of pancreatitis.²⁴

In a meta-analysis of systemic reviews comprising of 6,970 patients, the mortality rate reported was 35.2%.¹⁸ Jain et al.²⁵ in a prospective study in 206 AP patients reported 22% overall mortality with deaths among 52% patients with severe AP, particularly in those with multiple organ failure. Higher mortality (42%) was observed among patients with infected acute necrotic collections compared to infected walled-off necrosis (33%).

Patients with AP-related IPN frequently develop organ failure and therefore IPN may be associated with increased mortality,¹⁶ which can be further complicated by multidrug-resistant (MDR) microorganisms.²⁵ Thandassery et al.²⁶ in their study of 81 AP patients reported hypotension and APACHE II score at 24 hours of hospital admission as independent predictors of occurrence of IPN. The rate of infection correlates with the extent of pancreatic necrosis and its bacterial contamination. The immunologic mechanisms to prevent the proliferation of bacteria and fungi are absent in the necrotic tissue.

INFECTED NECROSIS VS STERILE NECROSIS

Microbial translocation is defined as the passage of both viable and nonviable microbes and microbial products across an anatomically intact intestinal barrier.²⁷ Translocation of viable microbes causes sepsis requiring antibiotic prophylaxis whereas nonviable bacterial products like pathogen-associated molecular patterns (PAMPs) cause systematic inflammatory response syndrome (SIRS) where antibiotic use is futile. In about half the number of AP patients, SIRS leads to multiple organ failure and subsequent death.

Clinically, there are no reliable parameters to distinguish infected from sterile necrosis. Microbial PAMPs such as lipopolysaccharides (LPS) activate innate immunocytes through pattern recognition receptors. The immune system also detects “danger,” through damage-associated molecular pattern (DAMP) molecules derived from other tissues. Thus, DAMPs stimulate an acute-phase response that is biologically concordant with PAMPs released during infection. This explains why it is difficult to distinguish infectious from noninfectious SIRS or to identify single molecules or molecular patterns of the host response that allow this distinction. Pathogen-associated molecular patterns cause infection when present on viable bacteria. Nonviable bacteria and bacterial products (LPS), which are released spontaneously upon exposure to various triggering factors like bacterial death by antibiotics, can be accompanied by an inflammatory response.²⁸ The clinical phenotype of a patient with sepsis may be similar to that of a patient with a SIRS caused by sterile inflammation like pancreatitis.²⁹

Bacterial infection of pancreatic necrosis can be seen in 30–50% of patients of necrotizing pancreatitis.³⁰ Clinical indicators for sepsis like fever and leukocytosis have been found to be higher among patients with IPN. The development of new onset fever, tachycardia, worsening SIRS, or organ failure should prompt evaluation for sepsis and suspicion of infected necrosis. The presence of gas or air bubbles in the collection is highly suggestive of infection but is present only in a minority of cases.³¹ Infection rates progressively increase with duration of the disease with highest incidence in the 3rd week. A direct correlation between extent of necrosis and incidence of infection has been demonstrated in a previous study where 56% of patients with more than 50% necrosis had infection as compared to 16.7% of those with less than 30% necrosis.³²

PANCREATIC VS EXTRAPANCREATIC INFECTIONS

Pancreatic infections may present itself as IPN that occurs earlier in the course of the disease or as infected pseudocysts and pancreatic abscesses that are the sequelae of acute necrotizing pancreatitis occurring more than a month after the acute episode. Infections in severe AP can be pancreatic or systemic and the prevalence usually correlates with the extent of pancreatic necrosis.^33,34 The probability of super infection of necrosis increases from 24% in the 1st week of the illness to 36% in the 2nd and 71% in the 3rd week.³⁵ Patients with extensive necrosis are at greater risk than those with focal necrosis. The main source of infections of the pancreas is direct translocation of bacteria from the large intestine.^36–38 During such times, the intestinal barrier fails, allowing the organisms to translocate to mesenteric lymph nodes, the systemic circulation, the portal venous circulation, the peritoneal cavity, and abdominal organs, with resulting supervening sepsis and critical complications. This could explain pancreatic infection with Escherichia coli, which is reported to be the most common organism in this setting.³⁹ The exact mechanism of bacterial translocation however is controversial and could be via lymphatics and consecutive hematogenous spread, or transmurally to the pancreas. Stress, like acute inflammation, renders the pancreas vulnerable to bacterial infections.

In the majority of patients, AP is generally mild and accompanied by minimal retroperitoneal inflammation and a peripancreatic fluid collection. In fact, AP is the setting for most infections of pancreas, which can complicate various stages of pancreatitis. In about 20% of the patients, peripancreatic fluid collection may be secondary to disruption of the pancreatic ductal system that later on develops into a pancreatic pseudocyst.³⁵ In 20–40% of patients with severe AP infection, pancreatic and peripancreatic necrosis may occur, leading to deterioration of organ functions.²³

Infection of the (peri) pancreatic necrosis occurs in about a third of these patients, which leads to 15–39% mortality rates.^5,40–43 Half of the mortality occurs later from complications secondary to the infection of (peri) pancreatic necrosis and the ensuing interventions.^22,44 In a study by Garg et al.,³⁹ extrapancreatic bacterial infections were found in 31.7% of 63 patients. In a multicenter audit from Italy, 56 of 161 patients with demonstrated pancreatic necrosis developed infection.⁴⁵ Bourgaux et al.⁴⁶ reported extrapancreatic infections in 25% of their AP patients. In a group of 713 patients, of whom only 154 had documented pancreatic necrosis, Besselink et al.²⁴ reported IPN in 98 patients, yielding an incidence of 63.3%. Petrov et al.¹⁶ in a meta-analysis of 14 studies comprising of 1,478 AP cases reported IPN in 314 (21%) patients, with an incidence in the individual reports ranging from 4% to 63%. Noor et al.³² observed pancreatic infections in 37.3% of patients and extrapancreatic infections in 62.7% of patients with severe AP with a significant increase in mortality.

Pando et al.⁴⁷ studied the role of extrapancreatic infections in the prediction of severity and local complications in AP and found that extrapancreatic infections played a role in predicting the severity and local complications in AP and when bacteremia and IPN occur, bacteremia preceded infected necrosis in all cases. Grajales-Figueroa et al.⁴⁸ demonstrated increased global mortality rate of 2.5% (57/2,227 AP patients) from extrapancreatic infections in hospitalized patients with AP over a period of 10 years.

ORGANISMS

The bacterial spectrum in IPN reflects the commensal flora of the intestine with predominantly gram-negative organisms such as E. coli, Pseudomonas aeruginosa, Proteus spp., and Klebsiella spp.³⁹E. coli is also reported in many other studies to be the most common isolate in pancreatic infections,^39,49,50 though in one study, Klebsiella was reported to be the most common isolate.⁵¹ However, at times, gram-positive bacteria viz. Staphylococcus aureus, Streptococcus faecalis, Enterococcus, and anaerobes have also been found accountable for pancreatic infections.^39,52,53 Monomicrobial infections were reported to be more common than polymicrobial. Isenmann et al.¹³ reported a polymicrobial prevalence of 15–40% among isolates. Furthermore, isolation of polymicrobial spectra should raise suspicion of fistula formation or bowel communication.

A change in the infective spectrum from gram-negative bacteria to that of gram-positive cocci and Candida especially in necrotizing pancreatitis patients on prophylactic antibiotics was reported by Isenmann et al.,⁵⁴ which was probably associated with increasing length of hospital stay or related to prophylactic antibiotics administration mainly targeting gram-negative bacteria.²⁴ Infections with gram-positive organisms occur later due to nosocomial bloodstream spread.³² Noor et al.³² studied 51 patients with severe AP and noted pancreatic infection in 19 (37.3%) patients (14 monomicrobial, 5 polymicrobial) with E. coli as the predominant organism. They also reported 21 positive blood cultures in 16 patients with severe AP and S. aureus was the predominant microorganism followed by E. coli, Enterobacter aerogenes, Alcaligenes xylosoxidans, E. faecalis, P. aeruginosa, Acinetobacter baumannii, and K. pneumonia.

Resistant bacterial isolates were detected in 15.6% of the necrotic collections in a study by De Waele et al.⁵⁵ However, more recent studies have shown an increasing incidence of MDR organisms in pancreatic infections. Jain et al.²⁵ reported culture positivity in 81% of 108 IPN patients with 86% growing MDR organisms. They reported E. coli in 48 (32%) and E. faecium in 10 (7%) of 149 isolates. Mowbray et al.⁵⁶ investigated the microbiology of 40 IPN patients and reported the most frequently identified microbes as E. faecalis (22.5%), E. faecium (20.0%), and E. coli (20.0%), with 19 cultures being polymicrobial. Sahar et al.⁵³ investigated the microbiology of infected walled-off pancreatic necrosis in 182 AP patients of which 41% were infected. Though MDR organisms was found in only five patients, Candida spp. accounted for 27%. Of those, 55% were infected, most frequently with Candida spp., Enterococcus spp., and coagulase-negative Staphylococcus. Around 85% had symptomatic sterile walled-off necrosis treated with minimally invasive therapy, enabling judicious selection of empiric antibiotic use.

Grajales-Figueroa et al.⁴⁸ demonstrated microbiological isolates in IPN in AP patients who died during hospitalization as Staphylococcus spp. (10 no.; 47.6%), E. faecium (9 no.; 42.8%), P. aeruginosa (7 no.; 33.3%), Candida spp., (6 no.; 28.5%), and E. coli (5 no.; 23.8%).

Würstle et al.⁵⁷ analyzed the spectrum of pathogens and their resistance to antibiotics as regards to the time course of the disease and its clinical outcome in 122 patients in Germany. They isolated 309 microorganisms (26 genera, 61 species) viz. Actinomyces spp., Aeromonas spp., Bacteroides spp., Citrobacter spp., Clostridium spp., Corynebacterium spp., Enterobacter spp., Enterococcus spp., Escherichia spp., Fusobacterium spp., Haemophilus spp., Klebsiella spp., Lactobacillus spp., Morganella spp., Neisseria spp., Parvimonas spp., Peptostreptococcus spp., Prevotella spp., Proteus spp., Pseudomonas spp., Rothia spp., Serratia spp., Staphylococcus spp., Stenotrophomonas spp., Streptococcus spp., and Veillonella spp. The authors also observed change at species level of E. faecalis to E. faecium and Candida albicans to non-albicans Candida spp. There was a 59.7% decrease in antimicrobial susceptibility in the overall number of patients with Enterobacteriaceae and a 46.0% increase in the incidence of MDR bacteria with increased length of hospital stay. A significantly higher mortality was observed for non-albicans Candida spp., E. faecium, and MDR bacteria suggesting that antimicrobial treatment of IPN becomes more challenging over time, due to an increase of multiresistant difficult-to-treat pathogens leading to worse clinical outcomes.

DIAGNOSIS

Infected pancreatic necrosis can be diagnosed mainly by laboratory methods as the clinical signs may be sensitive but not specific.^58,59 Clinically, there are no reliable parameters to distinguish infected from sterile necrosis as the clinical features are indistinguishable from other infectious conditions. Recently Qiu et al.⁶⁰ reported that artificial neural networks can accurately predict intra-abdominal infection in moderately severe and severe AP.

Laboratory methods for diagnosis of pancreatic infections are mentioned below:

PROPHYLACTIC ANTIBIOTICS

All standard guidelines do not recommend routine use of prophylactic antibiotics as no significant decrease in mortality and morbidity has been found with them.^72–76 This is supplemented by multiple meta-analyses that have showed no benefit with antibiotics.⁷⁶ The Japanese guidelines however recommend antibiotics in the severe pancreatitis in the 1st week. Pederzoli et al.⁷⁷ reported that antibiotic administration could prevent infections in patients with sterile necrosis.

Antibiotics are generally not given to patients with severe AP because of limited clinical benefits. However, antibiotics may be useful in some patients with severe AP having infected necrosis but are unfit for surgical debridement and drainage.⁵² Because of the use of antibiotics such as carbapenem and third-generation cephalosporins, MDR microorganisms have increased.^78–80

The incidence of MDR can be as high as 50% and microorganisms that are not covered by prophylactic antibiotic regimens become pathogens in subsequent infections. The emergence of MDR may be due to longer duration of antibiotic exposure. Thus, the use of prophylactic antibiotics to prevent pancreatic infection is not recommended. In view of the growing risk of MDR bacteria, antimicrobial prophylaxis has become a real challenge.^81,82 Lee et al.⁸³ reported MDR isolates in 29 of 46 IPN patients with no difference in mortality.

Nakaharai et al.⁸⁴ determined in a population-based study of 3,354 eligible patients in Japan if early prophylactic antibiotics improved the outcomes of severe AP patients and concluded that routine early prophylactic antibiotic use has no significant clinical benefit in severe AP patients but may increase the risk of hospital-acquired infections. Mowbray et al.⁵⁶ reported that antibiotics with the least resistance among the microbiota were teicoplanin (5.0%), linezolid (5.6%), ertapenem (6.5%), and meropenem (7.4%), and the latter two provide good antimicrobial cover against the common microorganisms causing IPN.

FUNGAL INFECTIONS

Recently fungal infections, particularly by Candida, are more and more being identified in severe AP. Risk factors to suspect fungal sepsis in AP include use of broad-spectrum antibiotics, central venous access, presence of renal failure, high APACHE scores, use of parenteral nutrition, diabetes mellitus, percutaneous drainage, and hospitalization beyond 4 weeks.⁸⁵ This negatively influences the clinical course of the disease with higher incidence of systemic complications leading to morbidity and mortality.^54,86–89 Demonstration of fungi in biopsy materials is the gold standard of diagnosis of a fungal infection. Grewe et al.⁹⁰ reported an estimation of about 10% of fungal association in pancreatic necrosis. Even though no significant mortality difference was reported by Gloor et al.,⁹¹ the authors suggest that the incidence could be increased multifold in recent years in hospitals where prophylactic antibiotics are routinely being used.⁹¹ De Waele et al.⁹² analyzed the association of fungal infections in an 8-year period data for 46 patients with severe AP and IPN and found intra-abdominal fungal infection in 17 (37%) of them with C. albicans in 15 patients and C. tropicalis and C. krusei in 1 patient each.

The pathogenesis of fungal infection in AP patients is multifactorial. Several reasons could attribute for increased incidence of fungal infection in AP, particularly increased use of broad-spectrum antibiotics⁵⁴ and the severity of the disease.⁹²Candida infection of 37% was reported by De Waele et al.⁹² and if patients who received early treatment were excluded, the incidence of Candida infection was as high as 50%.

Among fungal infections, Candida spp. is responsible for about 15–30% of pancreatic infections. The most common fungi are C. albicans, followed by C. tropicalis and C. krusei.⁸⁹ Jain et al.²⁵ observed fungal infection in 13% (27/209) of patients. Horibe et al.,⁹³ in a large multicenter cohort comprising of 44 institutions, investigated the impact of antibiotic prophylaxis for severe AP on the development of invasive pancreatic candidiasis. They observed that 1.9% of the 1,097 patients with severe AP had invasive pancreatic candidiasis and antimicrobial prophylaxis was significantly associated with the development of invasive pancreatic candidiasis. Würstle et al.⁵⁷ reported presence of yeasts in 41.0% of 122 acute necrotizing pancreatitis patients with C. albicans in 27.9%, whereas the incidence of non-albicans Candida spp. was only 13.9%.

ROLE OF ANTIFUNGAL TREATMENT

There is a lot of controversy regarding the role of antifungal treatment in AP. The risk factors for fungal infection in AP patients comprise of prolonged hospitalization, invasive methods, the use of broad-spectrum antibiotics, total parenteral nutrition, and mechanical ventilation. The risk associated with antifungal treatment, apart from the cost factor, is the selection of non-albicans species of Candida⁹² with decreased susceptibility or resistance to fluconazole and the induction of resistance in previously susceptible strains of C. albicans.⁹⁴ De Waele et al.⁹² reported development of C. krusei infection after prolonged fluconazole treatment in one patient. Thus, the use of antifungal treatment should be carefully considered for each patient, bearing in mind the potential drawbacks of apparently harmless prophylaxis.

However, antifungal treatment has been recommended for high-risk surgical patients due to the apparent increased mortality and morbidity after surgery. Antifungal prophylaxis with fluconazole was associated with a lower incidence of intra-abdominal fungal infection,^86,95 though it is not clear whether this data can be extrapolated to patients with severe AP. Pelz et al.⁹⁶ studied the efficacy of enteral fluconazole (400 mg) prophylaxis in 260 high-risk patients and reported a 55% reduction in the risk of acquiring fungal infection in the treatment group, though parenteral administration is advisable to ensure systemic efficacy.

De Waele et al.⁹² reported that though the characteristics of patients with and without fungal infections as well as the mortality rate were insignificant, early treatment with fluconazole could prevent fungal infection in their patients.

ANTIBIOTIC TREATMENT

The spectrum of pathogens isolated from the IPN helps to decide the choice of antibiotics. Most of the bacteria are sensitive to beta lactam antibiotics, aminoglycosides, and imipenem whereas application of broad-spectrum antibiotics bears the risk for a patient of AP to develop deep fungal infections.⁹⁷ Antimicrobial susceptibility test of selected microorganism helps determine the possible drug resistance in common pathogens and helps to assure susceptibility to drugs of choice for infections. Principles of antimicrobial stewardship include noticing changed pharmacokinetics in the critically ill, decreasing broad-spectrum therapy upon receiving culture reports, and early removal of antibiotics after establishing the source control. This will help to avoid the development of antimicrobial resistance, particularly in patients who may need frequent courses of antibiotics during the course of their disease.

Antibiotic therapy is indicated if pancreatic necrosis is suspected or confirmed on imaging. These patients have a 20–40% risk of superinfection in the retroperitoneum. The spectrum of pathogens isolated from the IPN helps to decide the choice of antibiotics. Another important deciding factor is the penetration of the antibiotic in the pancreas as selective uptake of various different classes of antibiotics occurs in the pancreas. Adequate tissue concentration in the pancreas occurs with fluoroquinolones, carbapenems, and metronidazole whereas ampicillin and gentamicin do not attain effective therapeutic levels in the pancreatic tissue. Metronidazole is suitable only as an adjunct agent for additional anaerobic coverage. The recommended antibiotics are either a combination of a quinolone (ciprofloxacin or ofloxacin) with metronidazole or, alternatively, monotherapy with imipenem–cilastatin.

In cases of infected AP, antibiotics are always recommended to treat the patients. Acylureidopenicillins and third-generation cephalosporins are effective against gram-negative microorganisms found in pancreatic infections.⁹⁸ However, for gram-positive organisms and anaerobes, only piperacillin/tazobactam is effective. Quinolones (ciprofloxacin and moxifloxacin) and carbapenems have the extra advantage of excellent anaerobic coverage apart from good tissue diffusion into the pancreas.⁹⁹ In terms of tissue penetration, carbapenems have the highest efficacy followed by fluoroquinolones and aminoglycosides. Hence, either of them is preferred for initial management. Appropriate application of antimicrobial treatment is required for treatment of severe AP, which is marked by organ failure and (peri) pancreatic necrosis with local complications such as infected necrosis. Leppäniemi et al.²³ in their guidelines for the management of severe AP suggest that quinolones should be used only in patients with allergy to betalactams because of their high rate of resistance and carbapenams should be used only in very critically ill patients after optimization due to dissemination of carbapenem-resistant K. pneumonia. The bactericidal antibiotic metronidazole also is capable of penetration into the pancreatic tissue. However, standard intravenous dosages of aminoglycoside antibiotics like gentamicin and tobramycin are unable to penetrate into the pancreas in required concentrations.¹⁰⁰

Longer duration of antimicrobial treatment in patients with severe AP is done in order to delay surgery. However, when the antimicrobial treatment is prolonged, there is a risk for consequent fungal infection or antibiotic resistance. Jain et al.²⁵ observed that among those who received prophylactic antibiotics, the rate of isolation of MDR organisms was not significantly different from those who did not receive prophylactic antibiotics.

OTHER MODES OF MANAGEMENT

The management of AP has developed considerably during the past decades. The preferred choices are primary conservative and minimally invasive modalities compared to open surgical necrosectomy^101–103 with decreased mortality.¹⁰⁴ In patients who are asymptomatic, strong suspicion of IPN would require interventions, even though some of them may recover with antibiotics only.¹⁰⁵ Wolbrink et al.¹⁰⁶ advocated invasive diagnostics (e.g., through FNA) for management of IPN in the intensive care unit, prior to the start of broad-spectrum antimicrobial therapy. Surgical necrosectomy with antifungal prophylaxis is the most widely used treatment modality.

ROLE OF PROBIOTICS

Initially in several experimental studies, the prophylactic use of probiotics in AP was investigated. van Minnen et al.¹¹⁸ reported reduced overgrowth of potential pathogens, decrease in bacterial translocation, and reduced mortality with probiotics use in rats with AP. There were two randomized controlled trials (RCTs) from Hungary regarding use of probiotics in AP. The first trial in 45 AP patients showed that probiotics reduced pancreatic sepsis and the need for surgical intervention.¹¹⁹ In the second trial with 62 severe AP patients, Olah et al.¹²⁰ concluded that nasojejunal feeding with synbiotics (inulin, beta-glucan, resistant starch, and pectin) may prevent organ dysfunction in severe AP.

Karakan et al.¹²¹ reported that supplementation of prebiotic fiber alone with enteral nutrition assessed in a randomized, double-blind study with 30 severe AP patients showed reduction of hospital stay, period of nutrition therapy, as well as overall complications compared to the usual enteral nutrition therapy. Besselink et al.¹²² reported a multicenter RCT where probiotics were compared with placebo in 298 patients with predicted severe AP. Probiotics were not found to reduce infectious complications, but rather increased the rate of bowel ischemia (9% vs 0%) and mortality (16% vs 6%) in the probiotics group. However, Qin et al.¹²³ reported that the patients with probiotic therapy showed less disease severity, improved gut permeability, and better clinical results.

Cui et al.¹²⁴ compared parenteral nutrition and enteral nutrition and the latter with the addition of the probiotic Bifidobacterium in 70 severe AP patients and reported that early enteral nutrition with Bifidobacterium resulted in reduced pro-inflammatory cytokines, improved gastrointestinal function, reduced complications, and shorter hospital stay. Gou et al.¹²⁵ studied the use of probiotics in severe AP by including six relevant human RCTs in which a total of 14 strains of probiotic bacteria were used. In total, Lactobacillus plantarum was used in three trials: B. longum, L. bulgaricus, L. paracasei, L. mesenteroides, and P. pentosaceus were used in different combinations in two trials, and B. bifidum, B. lactis, E. faecalis, L. acidophilus, L. casei, L. lactis, L. salivarius, and Streptococcus thermophilus used in just one trial. The authors concluded that probiotics showed neither beneficial nor adverse effects on the clinical outcomes of patients with predicted severe AP. But Wu et al.¹²⁶ investigated 120 patients with severe AP and found that probiotics could play a useful role in the treatment of severe AP. Bouwense et al.¹²⁷ observed that currently there was no place for probiotics as a treatment for AP. As there was a heterogeneity in the types of probiotics and treatment strategies used, even though previous data imply the potential of single specific probiotic strains supplemented, further appraisal about the role of probiotics is required.¹²⁸

CONCLUSION

A high index of suspicion is required for prompt diagnosis of pancreatic infections as early diagnosis and treatment can result in improved outcomes. Strict adherence to a rational antimicrobial treatment for patients with necrotizing AP is quite important. The antimicrobial therapy of IPN is more challenging with the length of the disease. Therefore, these patients can be managed well with appropriate diagnosis and identification of infection in order to improve the clinical outcome so that a change to narrow-spectrum antimicrobials can be done. Unnecessary antibiotic therapy without apparent proof of persisting infection should be avoided, as every antimicrobial treatment can lead to resistance, thereby complicating the treatment further. Other important preventive strategies include introduction of enteral nutrition and periodic change of vascular catheters. Furthermore, indications for surgical intervention should be defined and clinical trials on antifungal treatment are required.

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