Step-Up Approach to Acute Necrotic-Haemorrhagic Pancreatitis: Can Tigecycline Be Included

Step-up approach to acute necrotic-haemorrhagic pancreatitis: can tigecycline be included in antibiotic therapeutic strategy?

Morganti Lucia, Cultrera Rosario*, Occhionorelli Savino, Andreotti Dario, Maccatrozzo Stefano, Cappellari Lorenzo, Stano Rocco, Vasquez Giorgio.

Arcispedale Sant'Anna · Department of Surgery - Emergency Surgery Service, Ferrara ER Italy

*Arcispedale Sant’Anna·Department of Medicine-Infectious DiseaseDivision, Ferrara ER Italy

Background

Acute necrotic-haemorrhagic pancreatitis (ANP) is a severe and life-threatening disease whose prevalence is increasing nowadays. Necrotizing pancreatitis, which is associated with an 8 to 39% rate of death, develops in approximately 20% of patients[1]. The major cause of death, next to early organ failure, is secondary infection of pancreatic or peripancreatic necrotic tissue, leading to sepsis and multiple organ failure[2].

Although Atlanta International Symposium on Acute Pancreatitis[3] (1992) standardized this pathology definition, a worldwide full agreement concerning the therapeutic strategies is still lacking in antibiotic management and surgical procedure time-line.

UK guidelines (2005) were the last one for the management of acute pancreatitis: they agreed with a conservative approach to ANP, but didn’t talk about the use of US-guided drainage for the resolution of infected necrosis of the pancreatic gland[4]. The so-called “step-up approach” was introduced in 2006 with the “PANTER” study which consisted of percutaneous drainage, followed, if it’s necessary, by minimally invasive retroperitoneal necrosectomy[5].

Antibiotic strategy is still discussed; in literature there are no clear guidelines about when and what kind of antibiotics are best to use. Indeed, drug-induced acute pancreatitis is a rare entity that often is challenging for cliniciansand several antimicrobial agents are described to induce acute pancreatitis[6]. Recently, some authors pay attention on tigecyline-induced pancreatitis, trying to describe the possible pathogenesis. On the other side, McGovern presented a study that identified hospitalized subjects who developed pancreatitis in Phase 3 and 4 tigecycline trials: only 0.24% of 3,788 tigecycline-treated patients developed pancreatitis[7].

The present study investigates the option of including a clear antibiotic protocol which involves tygecycline, in association with quinolones and penicillin, in the management of ANP.

Methods & Patients

This retrospective analysis included 20 patients clinically homogeneous who referred to our Institution for ANP from March 2010 until July 2011.The study population was formed by 13 males (age range from 45 years old to 77 years old, with a mean age of 56.8) and 7 females (age range from 50 years old to 95 years old, with a mean age of 74). The overall mean age was 62.53 years old. The inclusion criteria were: 1) developing of severe stage, 2) clinical severity on admission, 3) conservative treatment of ANP.

Identifying criteria for ANP were: developing of systemic inflammatory- response syndrome (SIRS), multi-organ failure (MOF), CT images with gland necrosis and/or pancreatic and peripancreatic fluid collections, ICU admission, APACHE II score more than 8.

All of our patients have been treated according to our protocol:

-Admission to IUC if APACHE II score >8 and/or MEWS score > 4.

-Administrationof a broad spectrum antibiotic therapyshould start not more than 6-7 days.

-Antibiotic strategy switch in favour of tigecycline after 1 week of broad spectrum treatment failure and in case of associated positive cultural result. It was administrated to 4 four patients.

-First CT scan is done after almost 36-40 hours from symptoms upsets.

-US or CT scan- guided percutaneous drainage is performed to solve fluid collections or not-organized necrosis.

-Surgical debridment is indicated when all the previous approach have failed (worsening of clinical conditions and sepsis, despite the percutaneous approach and antibiotic treatment) and decompressive laparotomy is performed when intra-abdominal pressure (IAP) is > 20 mmHg.

-Follow-up after discharge ranges from 3 to 8 months, with a mean follow-up of 5.5 months. Patients lost in follow-up was seven: 2 dead, 2 not presented at first outpatient appointment, 3 not shown us back prescribed radiological controls.

A clinical records evaluation was performed highlighting clinical resolution, recovery time, short and long term complications, eventual death causes.

We treated 20 cases. Of them, only two patients underwent surgical debridement and they dead. Their death was in ICU after surgery, caused by lungs failure and septic shock. Moreover those patients had poor general clinical conditions and heavy comorbidity.

First days are crucial to diagnose, to assess disease severity and the possible evolution to severe stage. First of all, we request laboratory evaluation, paying attention to pancreatic enzymes increase, and also abdomen US and X-ray and chest X-ray, to make differential diagnosis with other disease with the same presentation symptoms. Then it’s important to check for blood cultures to compare them with the future ones, even they are either positive or negative. Thearterial blood gas (ABG) is useful to check for lung failure which is an indication for admission to ICU. An other useful score to admit patients to ICU is MEWS score (Modified Early Warning Score). MEWS score more than 4, is the cut-off for ICU admission [8]. The best severity scoring system to assess acute pancreatitis severity is Acute Physiology and Chronic Healt Evaluation (APACHE) II. An APACHE II score >8 determinate ICU transfer. We use both these scores for our patient while we avoid them if the initial clinical conditions left no doubt for ICU admission .We initiallyadminister big amounts ofliquidsto restorefluid and electrolyte balance, gabexate mesilate (Foy) and somatostatin (Stilamin). Finally, all the patients have a central venous catheter (CVC) for total parenteral nutrition and to check the central venous pressure (CVP).

Contrast- enhanced CT scan is the gold standard for severity assessment: Balthazar CT Severity Index4 is a radiological index which esteem both the extent of pancreatic necrosis and the number of abdominal fluid collections, denoting the intensity of the local inflammatory process. CT scan can also show the amount of pleural effusion. It is indicated to postpone the initial CT scan until 48-72 hours after symptoms onset in order to facilitate identification of necrotic areas and avoid underestimating severity. Indeed, the extent of necrosiscorrelates wellwith mortalityand therisk of developinglocal or systemic complications[9], [10]. We do the first CT scan after almost 36-40 hours from symptoms upsets and it shows, anyway, glandnecrosis, pancreaticandperipancreaticcollectionsand bilateral pleural effusion, indicating systemic involvement, typical of ANP.

We also check C-reactive Protein (CRP) levels during hospitalization as a severity index. CRP blood levels are usually low at admission, increase in 24-48 hours, with a peak at day 5. Then it goes down, according to the inflammation status and clinical patient condition. In our experience, CRP maximum peak is 41,5 mg/dl (normal range 0,00-0,50 mg/dl). CRP is monitored until discharge and it reaches normal levels only when the patient is fully recovered. Instead, levels of pancreatic enzymes decrease when CRP reach maximum peak. So we prefer using CRP to monitor pancreatic and systemic inflammation.

So in the first step, the focus is on vital signs support and SIRS control; then, when the patient is stable, we concentrate on pancreatic necrosis and fluid collections resolution and we try toavoid or to stop pancreatic necrosis infection.

Whit the infectivologist, we plan an antibiotics treatment strategy which follows the increasing level of surgeon’s aggressiveness in treating acute pancreatitis (Table 1). As the first step, we administer broad spectrum antibiotics (to control SIRS and sepsis); we reach the second step if blood cultures are positive and so we administer targeted antibiotic; third step is necessary if we have pancreatic fluid, drained by US or CT-guided percutaneous catheters.

Table 1

From cultures on these fluids, we can administer an even more targeted antibiotic therapy. We introduced tigecycline, in association with penicillin and quinolones, when cultures are positive or when clinical conditions get worse or don’t change after a week conventional antibiotic treatment or whenever there are evidences of intra-abdominal infection. Tigecycline was administrated in four cases, in conventional dosage for a medium period of 10 days.

We strictly checked every change in symptoms and laboratory index during the administration of tigecycline, aware of the known side effects. Tigecycline antibiotic treatment would be stopped in case of aggravation of pancreatitis-related symptoms. Our patients benefited from this antibiotic association which led to a complete resolution of pancreatitis related intra-abdominal infection. It was not necessary in any patients to give up with tigecycline treatment.

However, antibiotic treatment couldn’t be separated from US and/or CT- guided percutaneous drainage, which remove the infected fluid and, in this way, mitigate sepsis. These invasive technique is taken into consideration when radiological controls show the persistence offluid collectionsin thepancreatic andperipancreaticlodge, or when this fluid is infected, or when there is infected necrotic tissue. Infected necrotic tissue is definited as positive culture obtained by means of fine-needle aspiration or from first drainage procedure or from the presence of gas in fluid collection on CT scan.In our experience, this invasive procedurewasnecessary for 2 patients, which have fluid collection more than 2,5-3 cm diameter, who actually benefit from thistreatment.In all cases drained fluid reveled to be infected.

Finally, we trust in early enteral feeding with enteral nutrition formulas as it reduces bacterial translocation from the intestinal lumen to peritoneal cavity and decreases IAP, thanks to an early evacuation.

After discharging, we follow up our patients with radiological controls. In drained patients, US (after 7 days) are useful to check fluid collections evolution and if they were worsening, they could be drained again. CT scan is useful both to check patients after 1-2 months from recover and to evaluate forelectivecholecystectomy. In allcases, CT scan show the signs of the recent pancreaticinflammatory process, such asthe persistence ofcystsandpseudocystsand the thinningof partsof the gland; otherwise, signsofactive inflammationare absentandfluidcollectionsare significantlyreduced, ifnot completelydisappeared. Three patients undergo elective cholecystectomy, after 3-6 months from discharge. (Figure 1-3)

Figure 1

Figure 2

Figure 3

So to sum up: the mean follow up was 5.5 months after discharge.

Eight-teen patients (18/20) has a conservative approach with a mortality of 5.5% (1/18). Two patients need more invasive procedures as US/CT-guided percutaneous drainage of fluid collections. Only 2 (2/20) patients undergo surgical debridment with a mortality rate of 100% (2/2).Their death was in IUC after surgery, caused by lungs failure. Moreover those patients have poor general clinical conditions and heavy comorbidity.Four patients (4/18) was treated with tigecycline; no one of them died.

Antibiotics administration start according to general conditions, leukocytosis and fever. First choice broad spectrum antibiotic arebeta-lactamics and quinolones. As second choice we use tigecycline, in association to the first ones.

In four patients with resistant intra-abdominal infection, tigecycline has been successfully used, without complications or laboratory index alterations.

First CT scan was performed after 36-40 hours from symptoms onset and it shows severeinvolvementof the glandnecrosis, pancreaticandperipancreaticcollectionsand bilateral pleural effusion, indicating systemic involvement, typical of thesevere form.

Us and CT scan- guided percutaneous drainage is performed when radiological controls, done after almost a week, show the persistence offluid collectionsin thepancreatic andperipancreaticlodge. In particular, it wasnecessary for two patients, who had no complications but a significant improvement from thistreatment.

Conclusion

Infection is the most important factor which determinate prognosis and outcome of ANP and it is seen in 40-70 % of patient with necrotizing pancreatitis[11],[12],[13]. It is oftenpolymicrobialand involves bothaerobicand anaerobicbacteria, mainly fromintestinal flora such as Escherichia coli, Klebsiella, enterobacters, Proteus, Pseudomonas aeruginosa, Bacteroides, Clostridium and enterococci[14]. Empiric antibiotic therapies is correct if fever, leukocytosis and sepsis appears and always after doing blood and drained-fluids cultures.

UKguidelines stated that there are no consensus view on the value of antibiotic prophylaxis4. If it is used, it should be given for a maximum of 14 days. Treatment should not be continued beyond that time without evidence of infection provided by bacterial growth on culture. When such evidence exist, appropriate antibiotic therapy should be guided by the result of sensitivity testing in accordance with critical care guidelines[15].

As some studies demonstrated that prophylactic antibiotic therapy is not effective in the prevention of pancreatic necrosis infection, it is important to search for involved pathogens with blood and fluids cultures, drained by US and/or CT- guided percutaneous catheters1. Villatoro[16] et al published a review in 2010 that show a reduction in mortality if a b-lactam antibiotic is used as the first empiric choice, even though there is no evidenceofstatisticallysignificantreduction in the rateof necrosis infection.

Tigecycline is the first member of the glycylcycline class of antimicrobials. It was approved by the US Food and Drug Administration (FDA) in June 2005 for the treatment of complicated skin and

skin-structure infections (cSSSIs) and complicated intra-abdominal infections caused by susceptible Gram-positive, Gram-negative and anaerobic organisms. Tigecycline is structurally related to minocycline and shares similar pharmacokinetic properties and side effects with the tetracyclines. It is abacteriostatic, which interferes withprotein synthesisby bindingin a reversible way the30Sribosomalsubunitand preventingthe entry ofaminoacyl- t rna synthetase in the A site of theribosome[17]. Its activity appears not to beinfluenced bytwomajor mechanismsoftetracyclineresistance: ribosomalprotectionproteins, whichprevent antibiotics from interfering withprotein synthesis[18],andeffluxpumpsthat determine the rapid expulsionof the drugby bacteria, resulting in reducedeffectivenessof the antibioticitself[19]. It has activity towards methicillin-resistantStaphylococcus aureus, vancomycin-resistant enterococci15; concerning the intra-abdominal infection, it is active toward Citrobacter freundii, Enterobacter cloacae, Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae, Enterococcus faecalis, Staphylococcus aureus, Streptococcus anginosus, Bacteroides fragilis, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides vulgatus, Clostridium perfringens, e Peptostreptococcus micros[20]. Moreover, it is good in penetrating necrotic pancreatic tissue.

The most frequent adverse reactions associated with tigecycline are nausea, vomiting and diarrhea and, recently, some cases of pancreatitis have been associated with tetracycline[21]. Concerns about tigecycline-induced acute pancreatitis have recently been raised and some clinical cases about this topic are been published[22], [23], [24], [25],[26],[27].

Because of the structural similarity between tigecycline and tetracycline, it is possible that the same mechanism for tetracycline-induced pancreatitis could be the rationale for the episode of pancreatitis. None have clearly explained the exact mechanism of this reaction. Tetracycline induces hypertriglyceridemia, which cause pancreatitis[28]. Elmore and Rogger hypothesized that tetracycline block protein synthesis by disrupting the uptake of aminoacyl-transfer RNA on 30S ribosomial units. This results in accrual of triglycerides, precipitates an episode of pancreatits[29].Tigecycline is a derivative of tetracycline, and the two drugs have significant structural similarities, therefore it is quite plausible that the tigecycline molecule may react with the 30S ribosomial units via the mechanism as tetracycline molecule to precipitate an acute episode of pancreatitis26.However, tigecycline-induced acutepancreatitisisstill arare and under study phenomenon and it is considered an uncommon event, with an estimated incidence between 1% and 1‰21. High frequency of exposure to other medications associated with pancreatitis (prior to and concomitantly) occurred in tigecycline and comparator cases in similar proportions to that in non-cases7.

Prior and concomitant medications should be taken into consideration, but may not discriminate those who will develop pancreatitis6.

The American College of Gastroenterology’s guidelines (2005) do not recommend prophylactic antibiotics to prevent pancreatic infection in patients with mild acute pancreatitis. They approve the use of antibiotic therapy during the first 7-10 day from symptoms upset, while an evaluation for a source of infection is undertaken. If the cultures are negative, they suggest stopping antibiotic therapy1. To our experience, administrationof antibioticsshould start early and not more than 6-7 days after symptoms onset,with a broad spectrum antibiotic therapy; then, a targeted antibiotic treatment will be set up on the basis of blood or pancreatic fluids cultures.

In official guidelines1,4,[30], there’s no mention in using tigecycline. Our patients with infectednecrotizingpancreatitis, microbiologically documented, rapidlyimprovedwith the use oftigecycline, withreduction of complications.

In literature there are evidences about the efficacy of using tigecycline in treating complex intra-abdominal infection after acute pancreatitis complicated by intra-abdominal abscess. This is a new drug offering broad coverage and efficacy against resistant pathogens, and it can be added to clinical therapeutic arsenal[31]. However, large trials and multicentric studies are still necessary to fully understand the safety profile and efficacy of tigecycline.

References

1) Banks PA, Freeman ML: Practice parameters committee of the american college of gastroenterology. Practice guidelines in acute pancreatitis. Am J Gastroenterol 2006; 101:2379-2400.

2) Whitcomb DC: Acute pancreatitis. N Engl J Med 2006;354:2142-50.

3) Bradley EL 3rd: A clinically based classification system for acute pancreatitis. Summary of the international symposium on acute pancreatitis, Atlanta, Ga, September 11 through 13, 1992. Arch Surg 1993; 128(5):586-90.

4) Working Party of the British Society of Gastroenterology; Association of Surgeons of Great Britain and Ireland; Pancreatic Society of Great Britain and Ireland; Association of Upper GI Surgeons of Great Britain and Ireland: UK guidelines for the management of acute pancreatitis. Gut 2005; 54 (suppl 3):1–9.

5)Besselink MG, van Santvoort HC, Nieuwenhuijs VB, Boermeester MA, Bollen TL, Buskens E, Dejong CH, van Eijck CH, van Goor H, Hofker SS, Lameris JS, van Leeuwen MS, Ploeg RJ, van Ramshorst B, Schaapherder AF, Cuesta MA, Consten EC, Gouma DJ, van der Harst E, Hesselink EJ, Houdijk LP, Karsten TM, van Laarhoven CJ, Pierie JP, Rosman C, Bilgen EJ, Timmer R, van der Tweel I, de Wit RJ, Witteman BJ, Gooszen HG; Dutch Acute Pancreatitis Study Group: Minimally invasive 'step-up approach' versus maximal necrosectomy in patients with acute necrotising pancreatitis (PANTER trial): design and rationale of a randomised controlled multicenter trial [ISRCTN13975868]. BMC Surgery 2006; 6:6.