Gail Itokazu, Pharm.D.
Spring 1998

Intraabdominal Infections/Antimicrobial Prophylaxis in Surgery

  1. Etiology
  2. Antimicrobial Therapy
  3. Case 1

Required Readings

  1. DiPiro JT, et al. Intraabdominal Infections. In: Pharmacotherapy: A Pathophysiologic Approach. DiPiro JT, et al eds. Elsevier, NY, 1997. Chapter 107, pp 2145-2159.
  2. Janning SW, et al. Antimicrobial Prophylaxis in Surgery. In: Pharmacotherapy: A Pathophysiologic Approach. DiPiro JT, et al eds. Elsevier, NY, 1997. Chapter 115, pp 2305-2317.

Optional Readings

The following readings are not required, but may enhance your understanding of the material in this section.

  1. McClean EL, et al. Intraabdominal infection: a review. Clin Infect Dis 1994; 19:100-16.
  2. Bohnen JMA et al. Guidelines for clinical care: anti-infective agents for intra-abdominal infection: a surgical infection society policy statement. Arch Surg 1992; 127:83-89.

GOALS

  1. Understand the pathophysiology intraabdominal (IA) infections.
  2. Be able to recommend appropriate antimicrobial therapy for patients with IA infections.
  3. Understand the goals of therapy for patients with IA infections.
  4. Be able to recommend appropriate antimicrobial prophylaxis for specific surgical procedures.
  5. Understand the goals prophylactic antimicrobial therapy for patients undergoing surgical procedures.

INTRODUCTION

  1. Discuss the therapeutic management of IA infections.
  2. Discuss the difference between peritonitis and an intraabdominal abscess.

ETIOLOGY

  1. Discuss the difference between primary and secondary peritonitis.
  2. Discuss the difference in the microbial etiology of primary, secondary, and tertiary peritonitis.

Comments:

While E. coli and Bacteroides species are the common organisms causing secondary peritonitis, the microbial etiology of patients with tertiary peritonitis, severely ill patients with peritonitis, and patients with hospital acquired peritonitis or prior exposure to antimicrobials is different. In these groups of patients, the organisms isolated are more resistant to antimicrobial therapy.

a. Tertiary peritonitis is defined as persistent peritoneal infection that usually occurs in seriously ill patients with secondary peritonitis. The organisms associated with tertiary peritonitis are different from those associated with secondary peritonitis (are more resistant to antimicrobials) and include S. epidermidis, Enterococci, Pseudomonas species, and Candida species. Clinical signs of persistent IA sepsis include hypercatabolism, hemodynamic instability, and multiple organ dysfunction. (Article by McClean et al., in the optional readings provides additional information on tertiary peritonitis).

b. In severely ill patients (Apache II score >15) with peritonitis the most common organisms isolated include Candida species or other fungi (41-72%), Enterococcus species (31%), Enterobacter species (21-32%), Pseudomonas species (48%), and S. epidermidis (21-64%). Overall, Bacteroides species and E. coli were found less frequently, 7-12% and 17-24%, respectively (Am Surg 1992; 58:82-87. Can J Surg 1986; 29:247-50).

c. Patients with prolonged hospital stays (hospital acquired peritonitis) or prior exposure to antimicrobials are more likely to have peritonitis associated with Pseudomonas species, Enterobacter species, and Serratia species. (Clin Infect Dis 1994; 19:100-16).

Comment: Aerobic gram-negative bacilli such as Enterobacter, P. aeruginosa, Serratia, Citrobacter, Morganella and Acinetobacter species have a high propensity to develop resistance to all beta-lactams except carbapenems and cefepime when exposed to third generation cephalopsporins, though resistance to the cephalosporin cefipime has been reported. Beta-lactamse inhibitors (sulbactam, clavulanic acid, and tazobactam) also variably antagonize these organisms.

MICROFLORA OF GASTROINTESTINAL TACT AND FEMALE GENITAL TRACT

  1. Discuss the usual microflora of the gastrointestinal tract (Dipiro, Table 102.2, pg 1667).
  2. Discuss why serious intraabdominal infectious complications are not generally significant after perforation of the stomach.
  3. Know that the colon contains large numbers of aerobic (e.g. E. coli, Klebsiella) and anaerobic (Bacteroides spp, peptostreptococci) bacteria.

PATHOPHYSIOLOGY

  1. In primary peritonitis, discuss the mechanism via which bacteria gain entry into the abdomen.
  2. In secondary peritonitis, discuss the mechanism via which bacteria gain entry into the abdomen.

BACTERIAL SYNERGISM

  1. Discuss the results of animal models of IA infection that used various combinations of aerobes, anaerobes, and enterococci.
  2. List the top 4 aerobic and top 2 anaerobic bacteria found in IA infections.

CLINICAL PRESENTATION

  1. State at least 4 clinical and 4 laboratory signs of peritonitis.

TREATMENT

Left untreated, IA abdominal infections result in significant patient morbidity (sepsis, multiple organ failure) and mortality.

  1. Discuss the goals of treatment for patients with IA infections.
  2. Discuss the role of surgery in the management of IA infections.
  3. Discuss the rationale for fluid therapy in patients with IA infections.

ANTIMICROBIAL THERAPY

1. List the goals of antimicrobial therapy.

2. Discuss the antimicrobial treatment options for IA infections. As a guide, consider the following classes of antimicrobials: 1) aminoglycosides (gentamicin, tobramycin, amikacin), extended spectrum penicillins (mezlocillin, azlocillin, piperacillin), monobactam (aztreonam), beta-lactam/inhibitor combinations (ampicillin/sulbactam, ticarcillin/clavulanic acid, piperacillin/tazobactam), carbapenems (imipenem/cilastatin, meropenem), selected 2nd generation cephalosporins (cefoxitin, cefotetan, cefmetazole), selected 3rd generation cephalosporins (ceftazidime, cefoperazone), 4th generation cephalosporin (cefipime), quinolone (ciprofloxacin) and others (ampicillin, clindamycin, metronidazole).

Comment: Selection of antimicrobial regimens for the treatment of peritonitis should take the following into consideration: 1) is the infection considered secondary or tertiary peritonitis, 2) the severity of illness, 3) is the peritonitis hospital versus community acquired, 4) prior antimicrobial therapy, 5) the presence of immunocompromising conditions, and 6) the pathogens isolated.

While clindamycin has been traditionally incorporated into therapeutic regimens to treat the anaerobic component of IA infections, the prevalence of resistant of B. fragilis isolates to this antibiotic may be as high as 20-38% in some areas. Cefotetan and cefoxitin are 2nd generation cephalosporins with activity against members of the B. fragilis group of anaerobes. While they are used as monotherapy for IA infections, resistance to organisms in the B. fragilis group, particularly B. distasonis, B. ovatus, and B. thetaiotaomicron (sometimes referred to as the DOT group) may range from 16-53% in some areas [Clin Infect Dis 1993; 16(suppl 4):S357]. Thus, selection of antianaerobic agents may in part, depend on the hospital susceptibility patterns (if available) for these anaerobes.

3. Discuss the major toxicities of the following drugs: aminoglycosides (gentamicin, tobramycin, amikacin), imipenem, cefotetan, and cefmetazole.

Know the major route of elimination (renal vs hepatic) for the following drugs: aminoglycosides, aztreonam, and imipenem.

4. When might you consider monotherapy (single agent active against both aerobic and anaerobic organisms? When would you consider combination therapy in patients with IA infections?

Comment: Although agents such as cefoxitin, cefotetan, beta lactam/inhibitor combinations and carbapenems have activity against aerobes and anaerobes isolated in IA infections, there is still the possibility of aerobic gram-negative isolates which may be resistant to these agents. Therefore, some experts may initiate combination therapy with an aminoglycoside plus agents with both aerobic and anaerobic activity (e.g. beta-lactam/inhibitor, carbapenems, cefoxitin, cefotetan, ), and discontinue the aminoglycoside when culture results reveal susceptibility to the other agent.

5. How do clinical outcomes with monotherapy and combination regimens compare?

6. Discuss the controversy surrounding the use of ampicillin for coverage of enterococci in IA infections.

7. Discuss the difference in the duration of antimicrobial therapy for established IA infection vs acute IA contamination following traumatic injury.

EVALUATION OF THERAPEUTIC OUTCOMES

Comment: The duration of therapy will depend on the severity of infection, clinical response, and return of white blood cell count to normal. In one study, a persistent elevation in white blood cell count at the end of therapy was associated with a 33% incidence of recurrent IA sepsis and an additional 10% of patients had other nosocomial infections. If both an elevation in white blood cell count and fever were present, IA sepsis and nosocomial infections increased to 57% and 22% respectively (Ann Surg 1982; 195:19-24).

  1. Discuss reasons for poor outcome in patients with IA infections.
  2. Discuss the reason why a negative culture for anaerobes should not be the sole reason for discontinuation of anti-anaerobic drugs in patients with IA infections.
  3. Discuss reasons for antimicrobial failure.

Comment: Certain antimicrobials are less active under certain conditions. For example, aminolgycosides and clindamycin are less active in an acidic environment while beta-lactams are less active in the presence of high densities of bacteria.

ANTIMICROBIAL PROPHYLAXIS IN SURGERY - CHAPTER 115

Goals of Therapy:

  1. prevent infection when contamination with endogenous and exogenous bacteria is likely.
  2. Reduce morbidity and mortality associated with post-operative infection.

1. To be most effective in preventing post-operative infections, when should prophylactic antibiotics be administered?

2. How long are prophylactic antibiotics usually administered for?

3 Know the antibiotics recommended for surgical prophylaxis in the following surgeries: 1) gastroduodenal, 2) colorectal surgery, 3) cardiovascular.

Case 1:

CC: elective surgery on my colon

HPI: MM is a 75 year old female admitted for elective resection of her colon secondary to colon cancer. On the day of admission, physical exam and labs are within normal limits. The following bowel preparation is ordered: mechanical bowel preparation followed by oral erythromycin and neomycin 1 gram of each at 19, 18, and 9 hours before surgery. However, she becomes nauseated and unable to take her bowel preparation regimen, and really takes only 1 dose of each antibiotic. Although her surgery went well, within 24 hours after surgery she complains of diffuse abdominal tenderness. She appears very ill and septic, and is not expected to survive for more than 24 hours.

Physical exam: temp 104 degrees, pulse 120, respiratory rate 30/minute, B/P 90/50

HEENT: dry mucous membranes

ABDOMEN: distended and rigid, bowel sounds are absent.

Labs: WBC 40,000 with a differential of 60% segs, 20% bands, 15% lymphs, 5% others.

BUN 10mg/100ml, serum creatinine 1.0mg/100ml

1. What is her most likely diagnosis?

Based on the physical and laboratory findings, and the recent surgical procedure, secondary bacterial peritonitis is the most likely diagnosis. If you are unable to discuss the reasons for the abnormal findings on the physical examination, see page 2151, under "Treatment."

2. What empiric antibiotic(s) would you consider initiating? Why?

Her surgery involved the colon where both aerobes and anaerobes are potential pathogens. The ratio of anaerobes to aerobes is much higher in the lower gastrointestinal tract than the upper gastrointestinal tract. Thus, an antibiotic regimen should be active against both aerobes and anaerobes (ie: Bacteroides fragilis) found in the colon.

Potential regimens include:

monotherapy with a 2nd generation cephalosporin (cefoxitin, cefotetan, cefmetazole), beta-lactam/inhibitor combination (ticarcillin-clavulanic acid, ampicillin-sulbactam, piperacillin-tazobactam), or a carbapenem (imipenem-cilastatin, meropenem)

Comment: Since E. coli resistance to ampicillin/sulbactam may be as high as 60% in some institutions, this should be considered when used as monotherapy.

or

combination therapy with one of the agents listed above plus an aminoglycoside

or

combination therapy with an anaerobic agent (clindamycin or metronidazole) + an aminoglycoside, quinolone (ciprofloxacin)

or

aztreonam + clindamycin

Given the severity of MM's illness, combination therapy with an aminoglycoside plus a beta-lactam/inhibitor combination was ordered. Other aminoglycoside containing regimens that include an anti-anaerobic drug would also have been acceptable.

If clindamycin, cefoxitin, or cefotetan were selected for their antianaerobic activity, you should also take into consideration the prevalence of Bacteroides species resistant to these antianaerobic agents within the hospital.

3. If you selected a regimen containing an aminoglycoside, how would you minimize the potential toxicities associated with this class of antibiotics?

Monitor peak and trough serum levels to minimize neprho- and oto-toxicity. Administration of aminoglycosides as a single daily dose may also minimize nephro- and oto-toxicity; when administered as a single daily dose, some experts recommend maintaining aminoglycoside levels <1.0mcg/ml at 18 hours post-dose.

In addition to use of an aminoglycoside, what risk factor could also predispose this patient to renal insufficiency?

Intravascular volume depletion as evidenced by low blood pressure, tachycardia, dry mucous membranes. Thus, hydration would also be important in this patient.

4. If you selected a regimen containing imipenem/cilastatin, what important central nervous system toxicity you would monitor for, and how would you minimize this toxicity?

Seizures, modify dose with renal impairment.

5. Why was there an apparent failure of antimicrobial prophylaxis in MM's case?

The appropriate prophylactic regimen for MM's surgery was prescribed, however she failed to complete the entire regimen which probably accounted for the failure of prophylaxis.

6. Could this failure of prophylaxis have been prevented? If so, how?

Yes. MM could have received parenteral prophylaxis with cefotetan or cefoxitin. In cases where emergency surgery is required, and there is no time for prophylaxis with the oral regimen of neomycin, erythromycin, and mechanical bowel preparation, these parenteral cephalosporins are alternatives.

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