REVISED GUIDELINES ON THE MANAGEMENT OF INTRA- ABDOMINAL INFECTIONS John E. Mazuski, MD, PhD Professor of Surgery

Disclosures Contracted Research: Astra-Zeneca, Bayer, Merck Advisory Boards/Consultant: Bayer, Cubist, Pfizer Speaker: Merck, Pfizer

Objectives Provide an update on changes in the upcoming guideline for management of intra-abdominal infections: Discuss issues related to source control for patients with intra-abdominal infections. Outline options for antimicrobial therapy of intra- abdominal infections. New agents for resistant Gram negative Enterobacteriaceae. Duration of therapy.

The Surgical Infection Society Guidelines on Antimicrobial Therapy for Intra-Abdominal Infections: An Executive Summary John E. Mazuski, Robert G Sawyer, Avery B. Nathens, Joseph T. DiPiro, Moshe Schein, Kenneth A. Kudsk, and Charles Yowler, for the Therapeutic Agents Committee of the Surgical Infection Society Surgical Infections 2002; 3: Guidelines for the Selection of Anti-infective Agents for Complicated Intra-abdominal Infections Joseph S. Solomkin, John E. Mazuski, Ellen J Baron, Robert G Sawyer, Avery B. Nathens, Joseph T. DiPiro, Timothy Buchman, E. Patchen Dellingner, John Jernigan, Sherwood Gorbach, Anthony W. Chow, and John Bartlett Clinical Infectious Diseases 2003; 37:

Complicated Intra-abdominal Infection: Definitions Growth of pathogenic microorganisms in a normally sterile region of the abdominal cavity. Usually refers to secondary or tertiary peritonitis or an intra-abdominal abscess arising from a perforated viscus: Appendix. Colon or small bowel. Stomach or duodenum. Gallbladder. Postoperative. Solomkin JS, et al: Surg Infect 2010; 11:79; Clin Infect Dis 2010; 50:133

Generally involve transmural inflammation of a portion of the GI tract or its appendages. No extension of the infection beyond the hollow viscus. Microorganisms cannot be cultured from peritoneal or other surrounding fluid. If untreated, there is a substantial probability of these infections progressing to a complicated intra-abdominal infection. Uncomplicated Intra-abdominal Infections: Definitions Solomkin JS, et al: Surg Infect 2010; 11:79; Clin Infect Dis 2010; 50:133

Uncomplicated versus Complicated Intra-abdominal Infection? Early GI perforations? Contained diverticular or other GI perforations? Ischemic intestine?

SOURCE CONTROL

Why Source Control?

Solomkin JS, et al: Surg Infect 2010; 11:79; Clin Infect Dis 2010; 50:133 Why Source Control?

Several multivariate analyses have identified a failure to achieve adequate source control as a risk factor for treatment failure or death in patients with intra-abdominal infection. Surviving Sepsis and other guidelines also endorse early source control for control of intra-abdominal infection. Billing A, et al: Langenbecks Arch Chir 1992; 377:305 Wacha H, et al: Langenbeck's Arch Surg 1999; 384:24 Sotto A, et al: J Antimicrob Chemother 2002; 50:56 Mulier S, et al: World J Surg 2003; 27:379 Schneider CP, et al: World J Surg 2009; 33:34 De Waele JJ. Langenbecks Arch Surg 2010; 395:489 Marshall JC, et al: Crit Care Med 2004; 32[Suppl]:S513 Dellinger RP, et al: Intensive Care Med 2013; 39:165 Why Source Control?

A study of risk factors for mortality in 108 bacteremic patients with intra-abdominal infections. Overall mortality was 27.8%. Source control was achieved within 24 hours in 74/101 patients (73.3%). Mortality was 9.5% in those with adequate source control and 33.3% in those with inadequate source control, a 3.5-fold increase. In the multivariate logistic regression analysis, inadequate source control was highly associated with mortality (P = 0.011). Tellor B, et al: Crit Care Med 2012; 40[Suppl]:680 Why Source Control?

The Optimal Antimicrobial Agent Why Source Control?

“Drainage of abscesses or infected fluid collections” “Debridement of necrotic infected tissue” “Definitive measures to control a source of ongoing microbial contamination and to restore anatomy and function” Marshall JC: Microbes Infect 2004; 6:1015 Can We Manage IAI Without Definitive Source Control?

Approximately 3.8% of patients with appendicitis present with a peri-appendiceal mass (small abscess or phlegmon). Generally the result of a walled-off perforation. A more major procedure may be needed for operative treatment. Andersson RE, Petzold MG: Ann Surg 2007; 246:741 Management of the Peri-Appendiceal Mass due to Perforated Appendicitis

Meta-analysis of operative versus non-operative management (mostly non-randomized studies) (1.99, 5.64) Andersson RE, Petzold MG: Ann Surg 2007; 246:741 Management of the Peri-Appendiceal Mass due to Perforated Appendicitis

Meta-analysis of operative versus non-operative management (mostly non-randomized studies). Simillis C, et al: Surgery 2010; 147:818 Management of the Peri-Appendiceal Mass due to Perforated Appendicitis 0.24 (0.13, 0.44)

In selected circumstances, where the body has already controlled the infection and an operative procedure may result in significant morbidity: Perforated appendicitis. Perforated diverticulitis. Perforated peptic ulcer. Can We Manage IAI Without Definitive Source Control?

Utilization of less invasive approaches has been well established for patients with localized infections. Can We Manage Patients With Less Invasive Means of Source Control?

Percutaneous Drainage for Localized Intra-Abdominal Fluid Collections Overall initial success rate is 80-92%. Complication rates of 0-7%. Many unsuccessful initial drainage procedures can be salvaged with a second procedure. Operative management is needed in <5% of patients. Akinci D, et al: Cardiovasc Intervent Radiol 2005; 28:744 Theisen J, et al: J Gastrointest Surg 2005; 9:280

Currently, delayed debridement and use of temporizing drainage procedures is preferred for patients with infected pancreatic necrosis. Percutaneous Drainage for Infected Pancreatic Necrosis? Bakker OJ, et al: Curr Gastroenterol Rep 2009; 11:104 Mouli VP, et al: Gastroenterol 2013; 144:333 Mentula P, Leppäniemi A: World J Emerg Surg 2014; 9:15

Can We Manage Patients Diffuse Peritonitis With Less Invasive Means of Source Control?

Laparoscopic lavage and drainage, without colon resection, for perforated diverticulitis. 76% were Hinchey class III; 4% were Hinchey class IV. Alamili M, et al: Dis Colon Rectum 2009; 52:1345 Laparoscopic Lavage and Drainage for Hinchey Class III and IV Diverticulitis

Use of damage control laparotomy has been advocated based on experience in patients with severe abdominal trauma. Perform a limited procedure to control the infection. Resection without reanastomosis or ostomy formation. Temporary drainage as needed. Abdominal packing, if needed. Temporary abdominal closure. Rotondo M, et al: J Trauma 1993; 35:375 Solomkin JS, et al: Surg Infect 2010; 11:79; Clin Infect Dis 2010; 50:133 How Should We Manage Source Control in Critically Ill Patients?

Damage Control Laparotomy: Non-Controversial Indications Incomplete resection of ischemic bowel done to allow determination of viable versus non-viable bowel at a later time. Evidence of severe visceral edema placing the patient at risk for abdominal compartment syndrome. Solomkin JS, et al: Surg Infect 2010; 11:79; Clin Infect Dis 2010; 50:133

Damage Control Laparotomy: Other Potential Indications Failure to obtain adequate source control during initial laparotomy. Hemodynamic instability. Reassessment of the tenuous anastomosis. Diffuse peritonitis. Ordoñez CA, Puyana JC: Surg Clin N Am 2006; 86:1323 Weber DG, et al: Br J Surg 2014; 101: e109

Prospective Study of Staged Laparotomy Prospective randomized controlled trial comparing patients subjected to mandatory relaparotomy to patients undergoing on-demand relaparotomy for severe secondary peritonitis. No difference in overall mortality: Van Ruler O, et al: JAMA 2007; 298:865

In the on-demand laparotomy group: Only 43% of patients underwent one or more repeat laparotomies. 31% of repeat laparotomies were negative. Major morbidity was similar (40% versus 44%) Median ICU length of stay was shorter (7 days versus 11 days). Hospital median length of stay was shorter (27 days versus 35 days). There were 23% lower direct medical costs. Van Ruler O, et al: JAMA 2007; 298:865 Prospective Study of Staged Laparotomy

Source Control Source control remains important in the management of intra-abdominal infection. The necessity for and the adequacy of source control needs to be evaluated according to evolving contemporary evidence, and not according to rigid standards based on prior clinical experience.

ANTIMICROBIAL THERAPY: Selection of Agents

Antimicrobial Therapy: Treatment Goals With source control: Used as an adjunct to source control. Prevent dissemination of pathogenic microorganisms during source control procedures. Eradicate residual pathogens after those procedures. Without source control: The primary modality for the treatment of the infection. Marshall JC: Microbes Infect 2004; 6:1015

Antimicrobial therapy should include agents effective against aerobic Gram negative Enterobacteriaceae (e.g., E. coli), enteric Gram positive cocci (primarily streptococci), and enteric anaerobes (mainly Bacteroides sp.). Activity against enterococci, staphylococci, other Gram negative bacilli, and yeast under selected circumstances. Selection is based on assessment of patient’s individual risk factors for an adverse outcome, and the risk of resistant microorganisms in the local environment. Selection of Antimicrobial Therapy

Identify patients as having: Healthcare or hospital-associated infection: Currently hospitalized or previously hospitalized within 90 days for >48 h. Reside in a SNF or other long-term care facility. Receiving hemodialysis, IV infusion therapy, or complex wound care within the previous 30 days. Have received >48 h of broad-spectrum antimicrobial therapy within the previous 90 days. Community-acquired intra-abdominal infection: Without any of these risk factors Selection of Antimicrobial Therapy: Risk Assessment

For patients with community-acquired infections, stratify antibiotic selection according to patient risk: Higher risk patients: With severe sepsis/septic shock. Elevated APACHE II score (>10), if available. Multiple medical comorbidities. Problematic or delayed source control. Lower risk patients: Without any of these risk factors. Selection of Antimicrobial Therapy: Risk Assessment

Lower risk patients with community-acquired intra-abdominal infections: Narrower-spectrum therapy (E. coli, Bacteroides). No need for anti-enterococcal or antifungal therapy. Higher risk patients with community-acquired intra-abdominal infections: Broader-spectrum therapy. Selective use of anti-enterococcal and antifungal therapy. Patients with healthcare/hospital-associated intra-abdominal infections: Broader-spectrum therapy. Additional agents for resistant pathogens. Selection of Antimicrobial Therapy

Single agents: Ticarcillin/clavulanate. Ertapenem. Moxifloxacin (Serious β-lactam allergy). Combination regimens: Cefuroxime/ceftriaxone/cefotaxime plus metronidazole. Ciprofloxacin/levofloxacin plus metronidazole (Serious β-lactam allergy). Selection of Antimicrobial Therapy: Lower Risk Patients

Piperacillin/tazobactam. Broad-spectrum carbapenems: Imipenem/cilastatin. Meropenem. Doripenem. Ceftazidime/cefepime plus metronidazole (add ampicillin or vancomycin if anti-enterococcal coverage needed). Aztreonam plus metronidazole plus vancomycin (Serious β-lactam allergy). Add antifungal coverage if severely ill with a gastroduodenal source of infection. Selection of Antimicrobial Therapy: Higher Risk Patients

Anti-enterococcal coverage for expected pathogen: E. faecalis E. faecium Vancomycin-resistant Enterococcus Add MRSA coverage only if known to be infected or colonized with MRSA. Additional Gram negative coverage according to expected resistant pathogens (aminoglycoside, a polymyxin, or a tetracycline). Antifungal coverage with an echinocandin for patients at risk for Candida (recurrent GI perforations, surgically- treated pancreatitis, yeast colonization at multiple sites, repeated courses of broad-spectrum antibiotics. Selection of Antimicrobial Therapy: Healthcare/Hospital-Associated Infection

Fluoroquinolone-resistant E. coli is increasingly common. Susceptibilities of E. coli isolates from intra- abdominal infections to ciprofloxacin and levofloxacin: Hospital-associated IAI strains - 56%, 58%. Community-associated IAI strains - 71%, 72%. Fluoroquinolone Resistance Hawser SP, et al: J Chemother 2014; Epub

Distribution of fluoroquinolone-resistant E. coli is world-wide. Susceptibilities of E. coli isolates from intra- abdominal infections: Africa - 80%. Asia - 47%. Europe - 77%. Latin America - 52%. Middle East - 55%. North America - 72%. South Pacific - 80%. Fluoroquinolone Resistance Hawser SP, et al: J Chemother 2014; Epub

Recent studies of moxifloxacin or ciprofloxacin plus metronidazole for intra-abdominal infection have not detected increased failure rates with fluoroquinolones. Data from studies of urinary tract infection indicate increased failure rates when fluoroquinolone-resistant E. coli is treated with a fluoroquinolone. Importance of Fluoroquinolone Resistance?

Resistance of E. coli to various β-lactam antibiotics, mainly cephalosporins, has increased enormously over the past decade. Most extended-spectrum β-lactamases- producing strains remain susceptible to carbapenems. Some types of β-lactamases confer resistance to all β-lactam antibiotics, including carbapenems. β-Lactam Resistance

Resistance patterns of Gram negative pathogens isolated from patients with intra-abdominal infections in the Asia-Pacific region, Emerging Resistance of Gram Negative Bacilli in Asia 40.8% 21.5% Hsueh PR: Int J Antimicrob Agents 2012; 40[Suppl]:S1

ESBL prevalence in E. coli intra-abdominal isolates from Latin America ( ): Resistance of Gram Negative Bacilli in Latin America Hawser SP, et al: J Chemother 2012; 24:6

Resistance patterns of Gram negative pathogens isolated from patients with intra-abdominal infections in the Asia-Pacific region, Hsueh PR: Int J Antimicrob Agents 2012; 40[Suppl]:S1 Emerging Resistance of Gram Negative Bacilli in Asia Ceftriaxone Ceftazidime Cefepime Piperacilin/ Tazobactam Piperacilin/ Tazobactam Ertapenem Imipenem Cipro- floxacin Cipro- floxacin

Resistance of Gram negative intra-abdominal isolates in Latin America (2008): Susceptibility to carbapenems among ESBL-producing strains of E. coli and K. pneumoniae remains high. Resistance of Gram Negative Bacilli in Latin America Villegas MV, et al: Braz J Infect Dis 2011; 15:34

Although susceptibility of Enterobacteriacae to carbapenems remains high in Asia, resistance of other Gram negative bacilli to carbapenems is increasing. Kiratisin P, et al: Int J Antimicrob Agents 2012; 39:311 Emerging Resistance of Gram Negative Bacilli in Asia

Ceftolozane/tazobactam. Ceftazidime/avibactam. Newly-Approved Antibiotics

Newly-approved agent with enhanced anti- pseudomonal activity. May have some increased activity against β- lactamases. No anti-anaerobic activity. Efficacy of ceftolozane/tazobactam plus metronidazole was 83% compared to 87% for meropenem in a phase III trial. Equal efficacy to meropenem against ESBL-producing strains. Ceftolozane/Tazobactam Eckmann C, Solomkin J: Expert Opin Pharmacother 2015; 16:271

Enhanced spectrum of ceftazidime activity against many resistant mechanisms. No anti-anaerobic activity. Efficacy of ceftazidime/avibactam plus metronidazole was 91% and 92% compared to 93% for meropenem in phase II and III trials. Equivalent efficacy against ceftazidime-resistant strains. Newly approved by the FDA for treatment of complicated intra-abdominal and complicated urinary tract infections. Ceftazidime/Avibactam Lucasti C, et al: J Antimicrob Chemother 2013; 68:1183 Mazuski JE, et al:

A fluorocycline with activity against many resistant Gram negative pathogens. Comparable to ertapenem in phase II trial. Decreased efficacy of tigecycline is a concern. Eravacycline Solomkin JS, et al: Antimicrob Agents Chemother 2014; 58:1847 Phase II Trial Results:

ANTIMICROBIAL THERAPY: Duration of treatment

“Among available strategies to reduce use, reductions in length of antimicrobial regimens are the safest and are likely to be the most palatable to practicing clinicians.” Duration of Antimicrobial Therapy Rice LB: Clin Infect Dis 2008; 46:491

Prospective trial of 3 vs >5 days of antimicrobial therapy in 90 patients with low severity intra- abdominal infections. 50% with perforated appendicitis. Duration of Antimicrobial Therapy Basoli A, et al: J Gastrointest Surg 2008; 12:592

SIS STOP-IT trial of 4 days of antimicrobial vs. therapy until a complete clinical response (average 8 days) in patients with intra-abdominal infections who had adequate source control. 13% with perforated appendicitis. Mean APACHE II score was 10. Duration of Antimicrobial Therapy Sawyer R, et al: Surg Infect 2014; 15:S10

Summary Source control is still integral to the treatment of most patients with intra-abdominal infections, even though approaches and techniques are being modified. Selection of empiric antimicrobial therapy for patients with intra-abdominal infection needs to based on an assessment of patient risk and the potential for resistant pathogens. Duration of antimicrobial therapy can be significantly shortened (4 days).