Infectious Disease I: Intraabdominal Infections Courses in Therapeutics and Disease State Management

Learning Objectives (Slide 1 of 3) Define and describe the difference between primary, secondary, tertiary, complicated, and uncomplicated intraabdominal infections Define the terms abscess and peritonitis Describe the typical microbiology of intraabdominal infections

Learning Objectives (Slide 2 of 3) Describe the typical clinical presentation of peritonitis and intraabdominal abscess Describe the appropriate role of culture and susceptibility information for diagnosis and treatment of intraabdominal infections Describe the most appropriate drug and nondrug measures to treat intraabdominal infections Provide examples of antimicrobial agents that would be appropriate to treat a secondary intraabdominal infection such as an appendiceal abscess

Learning Objectives (Slide 3 of 3) Describe the appropriate antimicrobial treatment for a primary intraabdominal infection such as peritonitis associated with liver cirrhosis Describe the proper duration of treatment of an intraabdominal infection given details of the patient condition and type of infection Describe the proper assessment of patients during treatment of intraabdominal infections.

Required Reading Gross AE, DiPiro JT, Olsen KM. Chapter 92. Intraabdominal Infections. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic Approach, 9e. New York, NY: McGraw-Hill; 2014. Solomkin JS, Mazuki JE, et.al. Diagnosis and management of complicated intra-abdominal infection in adults and children: guidelines by the Surgical Infection Society and the Infectious Diseases Society of America. Clin. Infect. Dis. 210; 50:133–164.

Overview (Slide 1 of 2) Infection contained within the peritoneal cavity or retroperitoneal space Classification Generalized or Localized infections Uncomplicated or Complicated infections Community or Healthcare associated The peritoneal cavity extends from the undersurface of the diaphragm to the floor of the pelvis and contains the stomach, small bowel, large bowel, liver, gallbladder, and spleen. The duodenum, pancreas, kidneys, adrenal glands, great vessels (aorta and vena cava), and most mesenteric vascular structures reside in the retroperitoneum. Intraabdominal infections may be generalized or localized, complicated or uncomplicated, and community or healthcare-associated Uncomplicated intraabdominal infections are confined within visceral structure Complicated intraabdominal infections involve anatomical disruption, extend beyond a single organ, and yield peritonitis and/or abscess Appendicitis is one of the most common causes of intraabdominal infection. Most healthcare-associated intraabdominal infections occur as complications following intraabdominal surgeries.

Overview (Slide 2 of 2) Peritonitis Abscesses Primary Peritonitis Spontaneous Bacterial Peritonitis (SBP) Infection of peritoneal cavity without a source from the abdomen Secondary Peritonitis Source of bacteria is evident from within the abdomen May involve perforation of the GI tract Tertiary peritonitis An infection that persists or recurs at least 48 hours after apparently adequate management of primary or secondary peritonitis Occurs in critically ill patients Abscesses Result of chronic inflammation Located in the peritoneal cavity or in a visceral organ Risk factors the same as peritonitis Peritonitis is the acute inflammatory response of the peritoneal lining to microorganisms, chemicals, irradiation, or foreign-body injury Cirrhosis is one of the most common causes of primary peritonitis is adults. An abscess is a purulent collection of fluid separated from surrounding tissue by a wall consisting of inflammatory cells and adjacent organs. It usually contains necrotic debris, bacteria, and inflammatory cells.

Pathophysiology Primary Peritonitis is due to bacterial transmigration to the intraabdominal cavity via; Bloodstream Lymphatic system Transmigration through the bowel wall Indwelling peritoneal dialysis catheter Fallopian tubes in females Secondary peritonitis is due to bacterial entry via; Perforation of the GI tract Perforation of female genital tract Contamination during a surgical procedure  Anastomotic leak Abscess begins by the combined action of inflammatory cells bacteria, fibrin, and other inflammatory mediators Intraabdominal infection results from bacterial entry into the peritoneal or retroperitoneal spaces or from bacterial collections within intraabdominal organs Once bacteria enter into the peritoneal cavity, humoral and cellular defenses are activated and the omentum adheres to the affected area. A small bacterial inoculum is controlled quickly, but higher bacterial loads, the presence of foreign bodies, hematoma, necrotic tissue, continued bacterial contamination can impair the defenses of the body allowing the bacteria to spread. Bacterial spread through the intraabdominal space leads to widespread inflammation, adhesions, fibrin formation. This along with paralysis of the intestines (ileus) can result in the confinement of the infection to one or more locations within the peritoneum. Fluid and protein shifts may result in the movement of fluid from the circulating blood volume into the peritoneal space. This often results in a decreased circulating blood volume, decreased cardiac output, and hypovolemic shock Death from peritonitis is attributed to the combination of fluid shifts, cytokines, and endotoxin causing hypovolemia, hypoperfusion, and shock

Causes of Bacterial Peritonitis Primary (spontaneous) bacterial peritonitis Peritoneal dialysis Cirrhosis with ascites Nephrotic syndrome Secondary bacterial peritonitis (cont.) Mechanical GI problems Any cause of small bowel obstruction (adhesions, hernia) Vascular causes Mesenteric arterial or venous occlusion (atrial fibrillation) Mesenteric ischemia without occlusion Trauma Blunt abdominal trauma with rupture of intestine Penetrating abdominal trauma Peritoneal contamination during abdominal operation Secondary bacterial peritonitis (cont.) Miscellaneous causes Diverticulitis Appendicitis Inflammatory bowel diseases Salpingitis Biliary tract infections Necrotizing pancreatitis Neoplasms Intestinal obstruction Perforation Iatrogenic intestinal perforation (endoscopy) Intraoperative events Solid organ transplant in the abdomen Leakage from GI anastomosis Table 92-1 Causes of Bacterial Peritonitis

Normal Flora of GI Tract Approximate Concentration (Log No. Organisms/mL [×103/L]) Site Commonly Found Bacteria Aerobes Anaerobes Stomacha Streptococcus, Lactobacillus 10–100 Rare Biliary tract Normally sterile (Escherichia coli, Klebsiella, or enterococci in some patients) Proximal small bowel Streptococcus (including enterococci), E. coli, Klebsiella, Lactobacillus, diphtheroids 100 Few Distal ileum E. coli, Klebsiella, Enterobacter, enterococci, Bacteroides fragilis, Clostridium, peptostreptococci 104–106 105–107 Colon Bacteroides spp., peptostreptococci, Clostridium, E. coli, Klebsiella, enterococci, Enterobacter, Candida, and many others 105–108 109–1011 Table 92-2 Usual Microflora of the GI Tract aWith achlorhydria, acid suppressive therapy, gastric cancer, or gastric outlet obstruction, bacterial counts may rise to 105/mL

Common Pathogens Nosocomial Infection(%) Secondary Peritonitis(%) Community-Acquired Infection(%) Nosocomial Infection(%) Gram-Negative Bacteria Escherichia coli 32–61 29 22.5 Enterobacter 8–26 5.2 8.0 Klebsiella 6–26 2.8 4.5 Proteus 4–23 1.7 2.4 Gram-Positive Bacteria Enterococcus 18–24 10.6 18 Streptococcus 6–55 13.7 10 Staphylococcus 6–16 3.1 4.8 Anaerobic Bacteria Bacteroides 25–80 10.3 Clostridium 5–18 3.5 3.4 Fungi 2–5 3 4 Table 92-3 Pathogens Isolated from Patients with Intraabdominal Infection Because of the diverse bacteria present in the GI tract, secondary intraabdominal infections are often polymicrobia

Primary Peritonitis Varies greatly between patients Symptoms Signs Mild complaints Acute distress Symptoms Nausea Vomiting Abdominal tenderness Signs Hypoactive bowel sounds Mild fever Cirrhotic patients may have mental status changes Cloudy dialysate fluid in patients with Primary peritonitis can develop over a period of days to weeks and is usually a more indolent process than secondary peritonitis

Secondary Peritonitis Patients are often in acute distress Symptoms Nausea and Vomiting Abdominal guarding Signs Fever Tachypnea Tachycardia Faint to absent bowel sounds Sepsis

Laboratory, Radiology, and Microbiology WBC Ascitic Fluid Increase in Leukocytes Radiology Abdominal radiographs Microbiology Gram stain and Cultures of ascitic fluid Laboratory studies are not generally helpful in the diagnosis of intraabdominal abscess, although most patients will have leukocytosis Radiographic methods are used to make the diagnosis of an intraabdominal abscess

Goals of Therapy Correction of the intraabdominal disease processes or injuries that have caused infection Drainage of purulent collections Achieve a resolution of infection without major organ system complications Ameliorate clinical signs and symptoms Provide supportive care

General Approach to Treatment Surgical intervention and prompt drainage of abscesses Support of vital functions Early administration of empiric antibiotics that cover Gram negatives Anaerobes

Nonpharmacological Treatment Surgical correction of underlying pathology Respiratory and circulatory support as needed Aggressive fluid resuscitation therapy

General Approach to Empiric Antibiotic Therapy (Slide 1 of 3) Primary Bacterial Peritonitis Cirrhosis Most Frequent bacteria E. coli Klebsiella spp. Streptococci spp. Antibiotic Coverage choices 3rd Generation Cephalosporin Ceftriaxone Cefotaxime Ampicillin/Sulbactam Β-lactam allergy Ciprofloxacin IV Trimethoprim/sulfamethoxazole IV Optional add anaerobic coverage Metronidazole

General Approach to Empiric Antibiotic Therapy (Slide 2 of 3) Primary Bacterial Peritonitis Peritoneal Dialysis Most Frequent bacteria Staphylococcus aureus MSSA MRSA Streptococci spp. Gram negative enteric pathogens rare Antibiotic Coverage choices Combinations Cefazolin plus [Cefazidime or Cefepime or Aminoglycoside] Single Agents Cefepime Imipenem/cilastatin Β-lactam allergy Vancomycin plus aminoglycoside Ciprofloxacin (if local susceptibilities allow)

General Approach to Empiric Antibiotic Therapy (Slide 3 of 3) Primary Bacterial Peritonitis Peritoneal Dialysis Symptom onset slower which allows for gram stains and cultures MSSA Cefazolin IV Nafcillin/ oxacillin IV Β-lactam allergy Vancomycin IV Linezolid IV Daptomycin IV MRSA: Vancomycin in peritoneal dialysate Streptococcus or Enterococcus Ampicillin Gram negative Bacteria: Ceftazidime or cefepime

Primary Bacterial Peritonitis Treatment Course Deescalate antibiotics when cultures are finalized Oral agents can be used to complete the treatment Treatment Duration Traditional 10 to 14 days Peritoneal Dialysis patient should be treated for 14 days Prevention High reoccurrence rate of peritonitis in patients with cirrhosis Decrease in mortality and infection rate Antibiotic regimens Trimethoprim/sulfamethoxazole DS 1 tab PO daily for 5 days of the week Norfloxacin 400 mg PO Daily Ciprofloxacin 750 mg weekly or 500 mg Daily

General Approach to Empiric Antibiotic Therapy: Secondary Bacterial Peritonitis Perforated GI Tract Abscess Appendicitis Most frequent bacteria depends where perforation/ infection occurs Antibiotic Coverage choices Community-Acquired Complicated Intra-abdominal Infections Mild to Moderate infections High Severity Infections Hospital-Acquired Complicated Intra-abdominal Infections

Therapy should be active against Empiric Antibiotics for Mild to Moderate Severity Community Acquired Intraabdominal Infections (Slide 1 of 3) Therapy should be active against Enteric gram-negative aerobic and facultative bacilli Enteric gram-positive streptococci Coverage for anaerobic bacteria should be provided for distal small bowel, appendiceal, and colon-derived infections Combination or Monotherapy can be used Avoid anti-pseudomonal agents

Empiric Antibiotics for Mild to Moderate Severity Community Acquired Intraabdominal Infections (Slide 2 of 3) Mono-therapy β-lactam/β-lactamase inhibitor therapy Ticarcillin/ clavulanate Cephalosporins Cefoxitin Carbopenems Ertapenem Fluoroquinolones Moxifloxacin Glycylcyclines Tigecycline

Empiric Antibiotics for Mild to Moderate Severity Community Acquired Intraabdominal Infections (Slide 3 of 3) Combination therapy Cefazolin plus metronidazole Cefuroxime plus metronidazole Ciprofloxacin plus metronidazole Levofloxacin plus metronidazole

Empiric Antibiotics for High Risk Community Acquired Intraabdominal Infections (Slide 1 of 3) High Risk patients should be covered for Pseudomonas aeruginosa High Risk Patients High APACHE II Scores Poor nutritional Status Cardiovascular disease Immunosuppression Prolonged hospital stay

Empiric Antibiotics for High Risk Community Acquired Intraabdominal Infections (Slide 2 of 3) Mono-therapy Β-lactam/β-lactamase inhibitor therapy Piperacillin/tazobactam Carbopenems Meropenem Imipenem/cilastatin Doripenem

Empiric Antibiotics for High Risk Community Acquired Intraabdominal Infections (Slide 3 of 3) Combination Therapy Cefepime plus metronidazole Ceftazidime plus metronidazole Ciprofloxacin plus metronidazole Levofloxacin plus metronidazole

Empiric Antibiotics for High Risk Risk Hospital Acquired Intraabdominal Infections Patients that have risk factors for Multi drug resistant bacteria See Empiric Antibiotic lecture for list of risk factors Pseudomonas aeruginosa Use antipseudomonal agents If high resistance at institution consider double coverage Extended Spectrum β-lactamase producers MRSA

Secondary Bacterial Peritonitis Treatment Course Deescalate antibiotics when cultures are finalized Oral agents can be used to complete the treatment Treatment Duration Traditional 5 to 10 day courses

Clinical Outcomes Improvement in clinical signs and symptoms 2-3 days after antibiotics initiated Resolution of WBC Afebrile

Summary Intra-abdominal infections occur in the peritoneal cavity Empiric antibiotic therapy should be directed at gram negative and anaerobic pathogens Patient with alcoholic cirrhosis are at high risk for SBP caused by gram negative pathogens Patients with peritoneal dialysis are at risk for SBP caused by gram positive skin flora Patients with exposure to health care will require broadened empiric antibiotic coverage

References Gross AE, DiPiro JT, Olsen KM. Chapter 92. Intraabdominal Infections. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic Approach, 9e. New York, NY: McGraw-Hill; 2014. Solomkin JS, Mazuki JE, et.al. Diagnosis and management of complicated intra-abdominal infection in adults and children: guidelines by the Surgical Infection Society and the Infectious Diseases Society of America. Clin. Infect. Dis. 210; 50:133–164.