Guidelines for Clinical Care: Anti-infective Intra-abdominal Infection A
Agents for
Surgical Infection Society Policy Statement
John M. A. Bohnen, MD; Joseph S. Solomkin, MD; E. Patchen Dellinger, MD; H. Stephen Bjornson, MD, PhD; Carey P. Page, MD \s=b\ Several
antibiotics have been marketed for
therapeutic
in intra-abdominal infection. Often, these agents do not provide a sufficient spectrum activity against both facultative and obligate anaerobic gram-negative organisms, or have certain toxic effects that would not otherwise support their use. Guidelines have been developed for selection of antibiotic therapy for intra-abdominal infections and are use
presented as a statement of the Surgical Infection Society endorsed by the Executive Council. These guidelines are restricted to infections derived from the gastrointestinal tract and deal with those microorganisms commonly seen in such infections. The recommendations are based on in vitro activity against enteric bacteria, experience in animal models, and documented efficacy in clinical trials. Other concerns regarding pharmacokinetics, mechanisms of action, microbial resistance, and safety were also used in the formation of these guidelines. For community-acquired infections of mild to moderate severity, single-agent therapy with cefoxitin, cefotetan, or cefmetazole or ticarcillin\p=m-\clavulanicacid is recommended. For more severe infections, single-agent therapy with carbapenems (imipenem/cilastatin) or combination therapy with either a third-generation cephalosporin, a monobactam (aztreonam), or an aminoglycoside plus clindamycin or metronidazole is recommended. Regimens with little or no activity against facultative gram\x=req-\ negative rods or anaerobic gram-negative rods are not considered acceptable. (Arch Surg. 1992;127:83-89)
Intra-abdomi nal infections surgical practice
are common problems in and often result in substantial acute illness and mortality. Antibiotic therapy complements early diagnosis, a well-conceived and well-executed op-
Accepted
publication August 4, 1991. University of Toronto (Ontario) Faculty of Medicine, Department of Surgery (Dr Bohnen); Department of Surgery, University of Cincinnati (Ohio) College of Medicine (Drs Solomkin and Bjornson); Department of Surgery, University of Washington School of Medicine, Seattle (Dr Dellinger); and Department of Surgery, University of Texas Health Sciences Center, San Antonio (Dr Page). This article was prepared by the Antimicrobial Agents Committee of the Surgical Infection Society. Reprint requests to Department of Surgery, University of Cincinfor
From the
nati Medical Center, 231 Bethesda Ave (ML 558), 45267-0558 (Dr Solomkin).
Cincinnati, OH
erative procedure, and hemodynamic, respiratory, and nutritional support. Antimicrobial agents are important elements of therapy, serving to reduce the incidence of persistent or recurrent abscess or peritonitis and to decrease the incidence of infective wound complications. The true value of one anti-infective regimen vs another has, however, become difficult to substantiate in current practice because of the potency of currently available therapeutics. Relatively recent refinements in resuscitaand operative measures have themselves tive,
diagnostic,
significantly contributed to improved outcomes.1 A wide variety of anti-infective agents have been mar¬
keted for treatment of patients with intra-abdominal infections, often with marked differences in their anti¬ bacterial spectra, toxic effects, and cost. Guidelines for use of specific agents are not available because of problems in clinical research. Discussions of these problems have been published under the auspices of the Surgical Infection Society.2,3 Most notably, a variety of patient-specific fac¬ tors that are independent of anti-infective therapy affect outcome. These include preexisting medical conditions that may impair adaptive physiologic responses to the ef¬ fects of infection, the patient's resistance to the infection, the source and density of microorganisms, and the sever¬ ity of infection. Guidelines are also not available to aid the physician in making other, more complex therapeutic decisions. This is particularly true in such situations as the presence of uncommon or resistant organisms or apparent failure of the initial operative/antibiotic therapy. In these and other circumstances, insufficient clinical data exist to support
specific therapeutic strategies. This report was developed by the Antimicrobial Agents Committee of the Surgical Infection Society as a set of guidelines for selection of antimicrobial therapy for intraabdominal infections. This guideline is approved by the Executive Council of the Surgical Infection Society. Its purpose is to provide considered guidance to physicians caring for patients with intra-abdominal infection in regard to selection of appropriate anti-infective therapy. SCOPE AND DEFINITION OF INTRA-ABDOMINAL INFECTIONS For this article, intra-abdominal infection and secondary peritonitis are defined as the presence of a purulent exu-
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Table Facultative Cram-negative Bacilli
1.—Microorganisms Included
Facultative
Obligate Anaerobes Bacteroides fragilis
Escherichia coli Klebsiella species
Bacteroides
species species Morganella morganii Other enteric gram-negative species Enterobacter
Table 2.—Conditions That Do Not Require Antibiotic Therapy
Prolonged
Condition
Definition
Early acute appendicitis
Dull-red serosa, edema, induration of appendix As above with subserosal abscess formation; no gangrene, free
suppurative appendicitis
Simple acute cholecystitis Simple
dead bowel
Castroduodenal ulcer
perforation Traumatic enteric
perforations
perforation,
or
periappendiceal
abscess Acute inflammation;
no
perforation, pericholecystic abscess, or cholangitis
Transmural necrosis from
embolie, thrombotic,
or
obstructive vascular occlusion; no established peritonitis or abscess Perforation operated on within 24 h of onset Perforations operated on within 12 h of injury
date in the abdominal cavity derived from an enteric source.2 Intra-abdominal infections are described on the basis of the viscus giving rise to the infecting flora. The sites of origin for infections covered by these guidelines include the following: distal esophagus/stomach/ duodenum; biliary tree; proximal small bowel; distal small bowel; appendix; colon; liver; spleen; and pancreas (in¬ cluding both peripancreatic abscesses and the more un¬ common infected pseudocysts). Postoperative infec¬ tions within the abdomen constitute an important class of intra-abdominal infections. Liver and spleen ab¬ scesses need to be described in relation to cause, eg, secondary to diverticulitis, appendicitis, etc. Intraabdominal infections are then categorized on the basis
of findings at operation or by computed tomography or ultrasound examination as single abscess, multiple ab¬ scesses, and/or
peritonitis. Contiguous infection, such abscess arising in the gallbladder bed, is described as an abscess related to the primary organ site of infection. The bacteria covered by this guideline are detailed in Table 1. We have excluded from further consideration primary peritonitis (infected ascites), infections related to intraperitoneal catheters, extra-abdominal infection. These guidelines do not address conditions in which contami¬ nation has occurred but infection is not established, or conditions in which a largely localized infectious process as a
hepatic
Gram-positive Cocci Enterococci
species Fusobacterium species Clostridium species Peptococcus species Peptostreptococcus species Lactobacillus species
Proteus
Acute
in This Guideline Aerobic
Gram-negative Bacilli Pseudomonas aeruginosa
Staphylococcus species Streptococcus species
is treated by excision (Table 2). In these instances, antibi¬ otic therapy is prophylactic.4"8
PATHOGENESIS AND MICROBIAL CAUSE OF INTRA-ABDOMINAL INFECTION Microorganisms may contaminate the peritoneal cavity due to one or a combination of processes described as traumatic, neoplastic, vascular (ischemie), or inflamma¬ tory. The last category includes such conditions as gastroduodenal perforations due to peptic ulcer disease, Crohn's disease, ulcerative colitis, diverticulitis, intraluminal foreign bodies, peripancreatic infections after acute pancreatitis, appendicitis, and cholecystitis. The microflora encountered in the resulting infections are suffi¬ ciently similar to be grouped together when antimicrobial therapy is considered. Enteric, particularly colonie, sources of infection intro¬ duce hundreds of different bacterial species into the peri¬ toneal cavity, but only a limited number appear to persist at the site of infection. This appears due to different sus¬ ceptibilities to oxygen, serum proteins, and leukocytes and to toxin production. GENERAL ASPECTS OF ANTIMICROBIAL THERAPY IN ABDOMINAL INFECTION It must be clearly stated that the use of antimicrobial agents active against the infecting flora reduces the inci¬ dence of failure.9"11 Antimicrobial therapy may not result in an identifiable improvement in survival rates. The goals of anti-infective therapy are to reduce the incidence of persistent and recurrent intra-abdominal infection. Min¬ imizing drug complications and cost are considerations that should guide selection of agents with similar spectra of activity. In practice, treatment with antimicrobial agents is often begun when the diagnosis of intra-abdominal infection is suspected. This is often before an exact diagnosis is made and before results of appropriate cultures are available. The clinician must, therefore, anticipate the pathogens most likely to be encountered at the site of infection. Intra-abdominal infections require coverage of enteric gram-negative facultative and obligate anaerobic bacilli
(Table 1).
APPROPRIATE SPECIMEN HANDLING Intraoperative cultures are the primary basis for subse¬ quent decisions regarding antimicrobial therapy. Fluid collections, particularly if purulent, should be obtained for Gram's stain and culture. Specimens of infected intraabdominal fluid are either sent to the laboratory in a capped airless syringe with no needle or collected in ap-
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Table 3.—Antimicrobial Sensitivities of Commonly Encountered Pathogens to Parenteral Antibiotics Used in Abdominal Infection* Facultative
Organisms and Aerobes Gram-positive Cocci
Gram-negative
Obligate Anaerobes
Other
Bacilli
Enterococci
Streptococcus Species
0
+ +
+
Penicillin
Gram-negative Gram-positive Gram-positive Bacilli
Bacilli
Cocci
+ + +
+
+ + +
+ + +
Ampicillin Piperacillin
+ + +
+ + +
+
+ + +
+ + +
+ + +
+ + +
+ + +
+ +
+ + +
+ + +
Ticarcillint
+ +
+ +
+ + +
+ +
+ +
+ +
Cefazolin*
+ +
0
+ + +
+
+ + +
+ + +
Cefamandole§ Cefoxitinll
+ +
0
+ + +
+
+ +
+ + +
+ +
0
+ +
+ +
+ + +
+ + +
Cefotaximell
+ + +
0
+ +
+
+ +
+ + +
Imipenem
+ + +
+ +
+ + +
+ + -¬
+ + 4-
+ + -¬
Aztreonam
+ + +
0
0
Aminoglycosides# Clindamycin
+ + -¬
0
0
o
o
o
0
+ -¬
+ + +
+ + +
+ + +
+ + +
+ + +
+ + +
+ + +
+ + +
+ + +
+ + +
+ + +
+ + -¬
Metronidazole
0
0
+ +
+ + +
0
ß-lactamase inhibitorß-lactam combinations
Ampicillin-sulbactam
+ + +
Ticarcillin-clavulanic + + + + + acid + + indicates little or no activity; +, some activity; + + moderate to good tAzlocillin, mezlocillin, and carbenicillin have similar spectra. ilncludes cephalothin, cephapirin, and cephradine. §lncludes cefuroxime, cefonicid, cefotiam, and ceforanide. ¡Includes cefotetan and cefmetazole. Ulncludes ceftriaxone, ceftazidime, cefoperazone, and ceftizoxime. #lncludes gentamicin, tobramycin, netilmicin, and amikacin. ,
propria te separate aerobic and anaerobic transport media. If the Gram's stain reveals a predominance of grampositive cocci, which may indicate that Enterococcus or other fecal streptococci are significant copathogens at the
site of infection, the clinician should consider alterations in the antibiotic regime to include agents specifically ac¬ tive against Enterococcus.12 Appropriate management of Enterococcus is controversial. Some believe that specific anti-Enterococcus therapy should be given only when En¬ terococcus is the only isolate or in the presence of bacter¬ emia. If the Gram's smear reveals gram-negative bacilli, failure to isolate either facultative or obligate anaerobes on culture does not obviate the need to continue to provide
antimicrobial agents pital antimicrobial heeded when initial
against both.
Local or regional hos¬ susceptibility patterns should be empiric therapy is selected.1314
RATIONALE FOR SELECTION OF ANTIBACTERIAL AGENTS In vitro data, especially antimicrobial susceptibility tests, are predictive of the in vivo response of infecting bacteria to particular antibacterial agents. Although a va¬ riety of susceptibility testing techniques are available, disk or automated testing is appropriate for bacteria isolated from intra-abdominal infections except in extraordinary circumstances. Table 3 summarizes the in vitro suscepti¬ bilities of important pathogens to commonly used antiinfective agents in abdominal infection.
activity;
and
+
+, excellent
activity.
The combination of evidence from in vitro data, animal to widespread accep¬ tance of the need to provide empiric antimicrobial therapy directed against Escherichia coli and other common mem¬ bers of the family Enterobacteriaceae and Bacteroides fragijjS 9,i5,i6 Bacteroides fragilis and E coli are the most common isolates from intra-abdominal infections and are the organisms most likely to cause bacteremia in abdominal sepsis, further attesting to their pathogenicity.17 The evidence in support of broadening therapy to cover organisms other than common facultative and obligate anaerobes, such as E coli and fragilis, is more controver¬ sial. Initial empiric coverage of Pseudomonas aeruginosa is associated with a decreased likelihood of persistent or re¬ current abdominal infection if these organisms are iso¬ lated from the site of infection.18 Other clinical trials using anti-infectives not effective against aeruginosa have not found a high incidence of treatment failure with this or¬
studies, and clinical trials has led
ganism.19
ANTIMICROBIAL REGIMENS The recommendations described in these guidelines are based on a variety of factors. These include the in vitro data provided, experience in animal models, documented efficacy in meaningful clinical trials, and certain theoret¬ ical concerns regarding pharmacokinetics, mechanisms of action, and safety profile.
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Table
4.—Acceptable Antimicrobial Regimens
Single Agents Community-acquired infections of mild to moderate severity
Cefoxitin Cefotetan Cefmetazole Ticarcillin-clavulanic acid Severe infections
preferable to the recommended agents listed below. The combination of penicillin or ampicillin plus aminoglyco¬ side plus antianaerobe is recommended only if entero¬ coccal infection is suspected based on Gram's stain or thought to be clinically relevant (eg, associated with en¬ terococcal bacteremia). The choice for a particular patient will depend on the source of infection, the severity of the infection, the pa¬ tient's age, the degree of renal impairment, and local for¬ mulary considerations.
Imipenem-cilastatin Combinations
plus aminoglycosidet (young patient, no hypotension or renal compromise) Antianaerobe* plus third-generation cephalosporini Clindamycin plus monobactam§ *Antianaerobes include clindamycin or metronidazole. tAminoglycosides include gentamicin, tobramycin, netilmicin, Antianaerobe*
and amikacin. iCefotaxime and ceftizoxime. Ceftazidime and ceftriaxone are logical alternatives because of similar antimicrobial properties and lack of adverse effects; clinical data are insufficient.
§Aztreonam.
Not Recommended The following drugs should not be used as empiric therapy unless combined with acceptable agents listed below, because of inadequate coverage of both aerobic and anaerobic organisms: cefazolin and other firstgeneration cephalosporins, penicillin, cloxacillin and
antistaphylococcal penicillins, ampicillin, erythromycin, and vancomycin. Metronidazole and clindamycin should not be used alone because they lack activity against facultative enteric organisms. The following agents should not be used alone because of inadequate coverage of anaerobic gramnegative bacilli: aminoglycosides, aztreonam, polymyxother
ins, cefuroxime, cefonicid, cefamandole,
fotiam, cefotaxime, ceftizoxime, ceftriaxone, and ceftazidime.
ceforanide, cecefoperazone,
Because of inadequate clinical data documenting effi¬ cacy and concerns about resistance, the following drugs should not be used as single agents for empiric therapy despite their relative safety and broad in vitro antibacte¬ rial spectra: piperacillin, mezlocillin, azlocillin, ticarcillin, and carbenicillin. Certain agents have appropriate in vitro spectra of ac¬ tivity but serious toxic effects and are therefore not acceptable. Chloramphenicol is myelosuppressive and may lead to aplastic anemia.20 Moxalactam should not be used because of its potential to cause bleeding.21,22 For patients whose abdominal infection develops in the hospital after previous antibiotic therapy, cefoxitin, cefotetan, cefmetazole, cefotaxime, ceftriaxone, and cefti¬ zoxime should not be used because of the risk of resistant facultative gram-negative organisms. Newer agents, such as quinolones, should not be used until subjected to proper clinical trial.
Recommended Recommended regimens are listed in Table 4. Amino¬ glycosides are associated with the greatest toxic effects, especially in the elderly or patients with renal compro¬ mise, hypotension, and large cumulative dose, and re¬ quire serum level monitoring.2327 Cost or hospital formu¬ lary considerations may make one of these regimens
OTHER CONSIDERATIONS
Safety Antimicrobial agents may cause a wide variety of adverse effects, some of which are not dose related, such as anaphylaxis, and, more commonly, those that are re¬ lated to dose and duration of treatment. Preexisting med¬ ical conditions, such as renal failure and the severity of abdominal infection as manifested by shock, may increase the incidence and severity of drug complications. Com¬ mon, potentially harmful effects of antibacterial agents include immediate hypersensitlvity, nephrotoxic effects, ototoxic effects, coagulopathy, diarrhea, colitis often sec¬ and perhaps fungal superondary to Clostridium infection. Some effects have little potential for harm but may cause discomfort. Others pose diagnostic problems that may in turn prompt unnecessary and even invasive tests to exclude other sources of Clinicians should familiarize themselves with the adverse effects of antimicrobial agents that they use for treatment of intraabdominal infection.
difficile,
difficulty.
Resistance The
of anti-infective agents may result in the development of bacterial resistance. This can take the form of initially susceptible isolates becoming resistant during treatment or the appearance of other organisms resistant to the antimicrobial agents used.28,29 Individual patients may develop extra-abdominal nosocomial infec¬ tions with resistant organisms. An important factor promoting resistance of bacteria to anti-infective agents is the inappropriate use of such agents both inside and outside of hospitals. Indiscrimi¬ nate use must be avoided, and therapy should be contin¬ ued only as long as necessary. Acquisition of resistance during therapy with aminoglycosides is substantially less common than with the penicillins and cephalosporins.30 Therapy with "advanced-generation" penicillins and cephalosporins as single agents is as¬ sociated with the acquisition of resistant strains for Pseudomonas and Enterobacter species.28 If these organisms are identified, an aminoglycoside may be indicated. Drug-resistant organisms, including gram-negative fac¬ ultative bacilli, Enterococcus, Staphylococcus epidermidis, and fungi, are more likely to be encountered in recurrent abdominal infection than in a first episode.31 use
extended-spectrum
Cost
Assuming equivalent efficacy, safety, and potential for
resistance, the least expensive antimicrobial regimen should be chosen over others. The direct costs of drugs may be outweighed by the costs of treatment failure and adverse drug effects.
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Methods of Drug Administration Route.—Intravenous drug administration is routinely used to ensure absorption in patients with hemody¬ namic disturbances. The use of rectal, oral, or intra¬ muscular routes of administration is currently being ex¬ amined as completion therapy, and these routes are attrac¬ tive on the basis of cost. Intraperitoneal antimicrobial instillation, either during or after operation, remains con¬ troversial, with no clear evidence of benefit.32 Dose and Interval. —Recommendations provided in the package insert should be used as guides for deter¬ mining dose and dose interval. Most commonly used antimicrobial agents penetrate peritoneal fluid, and penetration is related to plasma concentrations. The minimum inhibitory concentration is commonly used to describe the activity of a given antibiotic against a particular organism. In this test, the concentration of antibiotic needed to prevent growth of bacteria is mea¬ sured and reported as micrograms per milliliter. Recent work has shown that efficacy of cephalosporins, peni¬ cillins, and other cell-wall-active antibiotics does not depend on the peak serum level but rather on the time during which serum levels are above the minimum inhibitory concentrations of the agent for the bacteria being treated.33-34 This supports the use of more fre¬ quent dosing intervals with lower doses. Because of the relative safety of these drugs, serum concentrations commonly exceed the minimum inhibitory concentra¬ tions for important organisms by several fold. Mini¬ mum inhibitory concentrations determinations are of value in determining antibiotic selection for patients
responding as anticipated. Efficacy of aminoglycoside therapy is related to the rapid achievement of "peak" serum levels four to eight times the anticipated minimum inhibitory concentra¬
not
tions.35 Without serum level monitoring, patients more commonly have subtherapeutic levels rather than toxic levels.36 Current dosing recommendations for amino¬ glycosides include initial dosing at 2 mg/kg for gentamicin, tobramycin, and netilmicin and 20 mg/kg for amikacin, with an initial dosing interval of 12 hours.30 Monitoring of aminoglycoside serum levels is necessary
ensure therapeutic peak levels and nontoxic trough levels. Determination of aminoglycoside peak and se¬ rum levels should be obtained on the first or second dose, and an early change to a therapeutic dose and dosing interval should be made. The common practice of beginning with low doses and adjusting upward results in prolonged delays in achieving therapeutic levels and is associated with an increased incidence of
to
failure.11-37 Duration.—Anti-infective agents are routinely given for 5 to 7 days for generalized peritonitis and localized abdominal abscess. In both categories of infection, an¬ timicrobial agents should be continued until tempera¬ ture and white blood cell count are within normal limits. Discontinuation of anti-infective agents while treatment
patient has fever or leukocytosis is associated with increased risk of recurrent or persistent abdominal infection.38-39 If clinical improvement is not evident within 4 days, or if fever or leukocytosis persists after more than 5 days of therapy, undrained abdominal infection or an inadequately treated extra-abdominal infection should be sought. the an
SPECIAL CONSIDERATIONS
Appendicitis The principles and recommendations for antimicrobial selection in gangrenous and perforated appendicitis and periappendiceal abscesses are as detailed above. The du¬ ration of antimicrobial therapy may be shorter for early acute and acute suppurative appendicitis. In these condi¬ tions, antibacterial treatment is prophylactic and should be begun before the incision to protect the surgical wound from infection. If the appendix is normal, or if it is inflamed but not perforated, the drug or drugs may be discontinued. If gangrene or perforation is found, the anti-infective regimen should be continued until the pa¬ tient has shown clinical improvement with return of bowel function, is afebrile, and has a white blood cell count below 12.0 109/L. Some infections, including diverticulitis without ab¬ scess formation and late appendicitis, may be treated without operation. In this case, antibiotic therapy as de¬ scribed above may be given for hospitalized patients. When a clinical response has been achieved, or if the pa¬ tient is being treated outside the hospital, oral therapy with a combination of agents effective against E coli and ß fragilis may be used. Amoxicillin plus clavulanic acid,
sulfamethoxazole-trimethoprim plus metronidazole, or a quinolone with metronidazole have appropriate in vitro spectra of activity, although no published data on this form of therapy are available.
Septic Complications of Acute Pancreatitis Acute pancreatitis itself may mimic infection with such findings as abdominal pain and tenderness, fever, and leukocytosis. However, the use of prophylactic antimi¬ crobial agents in uninfected acute pancreatitis is not rec¬ ommended. Computed tomography-guided percutane¬ ous aspiration is a reliable and safe method of distinguishing infected from uninfected pancreatitis. The presence of bacteria on Gram's stain or culture of aspi¬ rated material denotes infection. The diagnosis of pancreatic or peripancreatic infection is associated with either necrotic tissue, which requires débridement, or loculated fluid collections, which require drainage. In these circumstances, antimicrobial therapy should be administered as described above, with therapy continued until clinical improvement occurs along with normalized temperature and white blood cell count. There appears to be a risk of acquisition of drugresistant organisms due to superinfection, and cultures should be obtained during each reoperation. Therapy should be guided by results of these cultures. The initial choice of antimicrobial regimen should be based on Gram's stain and culture of infected tissue or fluid taken by percutaneous aspiration or at operation. Ini¬ tial empiric coverage, as in other types of abdominal infection, should include E coli and other aerobes, plus fragilis and other anaerobes. Fungal Peritonitis Candida species may be identified in infected intraabdominal fluid. When fungi are isolated at the first operation for community-acquired intra-abdominal sep¬ sis, therapy with amphoterìcin is not recommended. In patients who have recently received immunosup¬ pressive agents, such as steroids or antineoplastic ther-
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apy,
or
in
patients with recurrent intra-abdominal in¬ is a significant risk of progressive fungal
fection, there
infection if Candida is isolated from intra-abdominal cul¬ tures, and amphoterìcin therapy improves outcome results.40-41
Tertiary or Recurrent Peritonitis In patients with recurrent or persistent abdominal infection, the infecting bacteria may be resistant to anti¬ microbial agents used in initial, empiric therapy.31-42 Treatment must be individualized, depending on previ¬ ous culture reports and local antimicrobial sensitivity patterns. Aminoglycosides may be the agents of choice for any facultative gram-negative organisms identified. Clinical Failure If abdominal infection appears to persist, a focus of in¬ fection that requires drainage is the usual cause. Treat¬ ment failure should be suspected if there is not substan¬ tial resolution of fever, and ileus by the 3rd or 4th postoperative day. The clinical signs of persistent or recurrent abdominal infection may be mimicked by extra-abdominal infection and by a variety of noninfectious processes, including thrombophlebitis and drug fe¬ ver. Persistent or recurrent illness mandates a thorough examination and search for a drainable focus of infection within the abdomen, including noninvasive imaging studies, such as computed tomography or ultrasound ex¬ aminations. If one or more microorganisms isolated at the initial intervention is not susceptible to the antibiotics provided, a change of antimicrobial agents to provide such coverage is indicated. However, rarely will a change in antibiotics effect resolution of persistent or recurrent abdominal sepsis.
leukocytosis,
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26. Kacew
51:241-259. 27. Meyers
BR, Wilkinson P. Clinical pharmacokinetics of antibacterial drugs in the elderly: implications for selection and dosage. Clin Pharmacokinet. 1989;17:385-395. 28. Sanders WE Jr, Sanders CC. Inducible beta-lactamases: clinical and epidemiologic implications for use of newer cephalosporins. Rev Infect Dis. 1988;10:830-838. 29. Bauernfeind A, Horl G, Monch V. Changes in microbial ecology by therapeutic use of aminoglycosides. Scand J Infect Dis. 1986;49(suppl):106-114. 30. Ho JL, Barza M. Role of aminoglycoside antibiotics in the treatment of intra-abdominal infection. Antimicrob Agents Chemother. 1987;31:485-491. 31. Rotstein OD, Pruett TL, Simmons RL. Microbiologic features and treatment of persistent peritonitis in patients in the intensive
care
unit. Can
Downloaded From: http://archsurg.jamanetwork.com/ by a New York University User on 06/21/2015
J Surg. 1986;29:247-250.
32. Schein M, Saadia R, Decker G. Intraoperative peritoneal lavage. Surg Gynecol Obstet. 1988;166:187-195. 33. Leggett JE, Fantin B, Ebert S, et al. Comparative antibiotic dose-effect relations at several dosing intervals in murine pneumonitis and thigh-infection models. J Infect Dis. 1989;
159:281-292. 34. Vogelman B, Gudmundsson S, Leggett J, Turnidge J, Ebert S, Craig WA. Correlation of antimicrobial pharmacokinetic parameters with therapeutic efficacy in an animal model. J Infect Dis. 1988;158:831-847. 35. Moore RD, Lietman PS, Smith CR. Clinical response to aminoglycoside therapy: importance of the ratio of peak concentration to minimal inhibitory concentration. J Infect Dis.
1987;155:93-99. 36. Li SC, loannides Demos LL, Spicer WJ,
et al. Prospective usage in a general hospital with assessments of clinical processes and adverse clinical outcomes. Med J Aust. 1989;151:224-232. 37. Moore RD, Smith CR, Lietman PS. Association of amino-
audit of
aminoglycoside
Invited This is a well-thought-out position paper providing sound advice about choosing among the surfeit of antibiotics cur¬ rently available to treat patients with infections in the abdo¬ men. It also provides an important message about a matter once controversial but no longer in dispute: the spectrum of antibiotics chosen must cover both aerobes and anaerobes to achieve success. The treatment of intra-abdominal infections encompasses some still-controversial issues about which experts differ. Even though I chaired the Executive Committee of the Sur¬ gical Infection Society at the time the society approved this position paper, there are some points in this report to which I would take exception. Let me first emphasize that the pa¬ per contains very solid advice that, if followed, will help cure suffering intra-abdominal infection. Having said patients that, let me illustrate the nature of my exceptions by discuss¬ ing two points: the role of Enterococcus in abdominal infection and apparent differences in efficacy against E coli between ß-lactamase inhibitor antibiotic combinations. Even though ignored in this paper, the pathogenic role of Enterococcus in a polymicrobic abdominal infection continues to be a matter of controversy. Controversy arises because En¬ terococcus is not a vigorous pathogen; it has comparatively poor capacity to invade and persist in tissue. Enterococci do not produce toxins or destructive enzymes, as do other gram-positive organisms, and they lack the capacity to exclude other bacteria actively from their environment as, for Rather, Enterococcus is a sur¬ example, E coli does so vivor organism, often persisting because it is widely resistant to many antibiotics. When considering the pathogenic role of Enterococcus, it is important to distinguish between monomicrobic and poly¬ microbic infections. In monomicrobic situations, such as bac¬ terial endocarditis, in which Enterococcus is the only organism recovered, it clearly is acting as a pathogen and requires pri¬ mary treatment. However, in the context of abdominal infec¬ tions that are polymicrobic in nature, and in which Enterococ¬ cus is only one of many species of bacteria present, it rarely acts as a primary pathogen. However, enterococci will persist if initial treatment of the infection fails. When such a clinical course is predictable, as in immunocompromised patients, then coverage of Enterococcus as a part of initial therapy is reasonable. But, for most patients, antibiotic therapy cover¬ ing enterococci in intra-abdominal infections is not necessary,
readily.
glycoside plasma
levels with therapeutic outcome in gram\x=req-\ Am J Med. 1984;77:657-662. 38. Lennard ES, Dellinger EP, Wertz MJ, Minshew BH. Implications of leukocytosis and fever at conclusion of antibiotic therapy for intra-abdominal sepsis. Ann Surg.
negative pneumonia.
1982;195:19-24. 39. Lennard ES, Minshew BH, Dellinger EP, Wertz M. Leuko-
cytosis at termination of antibiotic therapy: its importance for intra-abdominal sepsis. Arch Surg. 1980;115:918-921. 40. Solomkin
JS, FlohrA, Simmons RL. Candida infections in
surgical patients:
dose requirements and toxicity of amphotericin B. Ann Surg. 1982;195:177-185. 41. Solomkin JS, Flohr AB, Quie PG, Simmons RL. The role of Candida in intraperitoneal infections. Surgery. 1980;88:524\x=req-\ 530. 42. Walsh GL, Chiasson P, Hedderich G, Wexler MJ, Meakins JL. The open abdomen: the Marlex mesh and zipper technique: a method of managing intraperitoneal infection. Surg Clin North Am. 1988;68:25-40.
Commentary nor
is the addition of antienterococcal coverage needed if ini¬
peritoneal cultures yield enterococci but the patient clin¬ ically is doing well.1 My second quibble concerns the recommendation of ticarcillin-clavulanic acid in preference to ampicillintial
sulbactam, based
on the apparent resistance of some strains of E coli to ampicillin-sulbactam. It is increasingly apparent that the difference in coliform sensitivity to these drugs is in¬ fluenced by the methods used to measure sensitivity and re¬ sistance in the laboratory. The disks used to measure the ef¬ ficacy of these antibiotics are not identical; the ticarcillinclavulanic acid disk contains 75 µg of ticarcillin, whereas the ampicillin-sulbactam disk contains 10 µg of ampicillin. The difference in functional antibiotic concentration has the potential to alter apparent sensitivity (false resistance) when the efficacy of the two drug combinations is compared. Were it not for the artifactual deficit in efficacy against coliforms, ampicillin-sulbactam theoretically would be preferred be¬ cause it is more active against staphylococci, the sulbactam component is an active antibiotic in its own right (although a weak one), and sulbactam does not compete for penicillinbinding sites as does clavulanic acid. In fact, both drugs are equally efficacious in treating abdominal infections, and the differences between them are clinically unimportant. There¬ fore, I would appropriately update the information contained in Table 3 and broaden the recommendations contained in Table 4. My comments are offered primarily so that readers will be aware that, as is true of most clinical situations, all is¬ sues are not totally settled. Optimal therapy will change in evolutionary ways as new information about bacterial patho¬ genesis and antibiotic efficacy is acquired. It continues to be important for physicians to keep current with the new infor¬ mation continuously available in the literature. This Surgical Infection Society position paper provides a solid base on which to build a future framework of knowledge. Robert E. Condon, MD, MS Milwaukee, Wis
Reference 1. Barie
PS, Christou NV, Dellinger EP, Rout WR, Stone HH, Waymack JP. Pathogenicity of the Enterococcus in surgical infections. Ann Surg. 1990;212:155-159.
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Agents for
Surgical Infection Society Policy Statement
John M. A. Bohnen, MD; Joseph S. Solomkin, MD; E. Patchen Dellinger, MD; H. Stephen Bjornson, MD, PhD; Carey P. Page, MD \s=b\ Several
antibiotics have been marketed for
therapeutic
in intra-abdominal infection. Often, these agents do not provide a sufficient spectrum activity against both facultative and obligate anaerobic gram-negative organisms, or have certain toxic effects that would not otherwise support their use. Guidelines have been developed for selection of antibiotic therapy for intra-abdominal infections and are use
presented as a statement of the Surgical Infection Society endorsed by the Executive Council. These guidelines are restricted to infections derived from the gastrointestinal tract and deal with those microorganisms commonly seen in such infections. The recommendations are based on in vitro activity against enteric bacteria, experience in animal models, and documented efficacy in clinical trials. Other concerns regarding pharmacokinetics, mechanisms of action, microbial resistance, and safety were also used in the formation of these guidelines. For community-acquired infections of mild to moderate severity, single-agent therapy with cefoxitin, cefotetan, or cefmetazole or ticarcillin\p=m-\clavulanicacid is recommended. For more severe infections, single-agent therapy with carbapenems (imipenem/cilastatin) or combination therapy with either a third-generation cephalosporin, a monobactam (aztreonam), or an aminoglycoside plus clindamycin or metronidazole is recommended. Regimens with little or no activity against facultative gram\x=req-\ negative rods or anaerobic gram-negative rods are not considered acceptable. (Arch Surg. 1992;127:83-89)
Intra-abdomi nal infections surgical practice
are common problems in and often result in substantial acute illness and mortality. Antibiotic therapy complements early diagnosis, a well-conceived and well-executed op-
Accepted
publication August 4, 1991. University of Toronto (Ontario) Faculty of Medicine, Department of Surgery (Dr Bohnen); Department of Surgery, University of Cincinnati (Ohio) College of Medicine (Drs Solomkin and Bjornson); Department of Surgery, University of Washington School of Medicine, Seattle (Dr Dellinger); and Department of Surgery, University of Texas Health Sciences Center, San Antonio (Dr Page). This article was prepared by the Antimicrobial Agents Committee of the Surgical Infection Society. Reprint requests to Department of Surgery, University of Cincinfor
From the
nati Medical Center, 231 Bethesda Ave (ML 558), 45267-0558 (Dr Solomkin).
Cincinnati, OH
erative procedure, and hemodynamic, respiratory, and nutritional support. Antimicrobial agents are important elements of therapy, serving to reduce the incidence of persistent or recurrent abscess or peritonitis and to decrease the incidence of infective wound complications. The true value of one anti-infective regimen vs another has, however, become difficult to substantiate in current practice because of the potency of currently available therapeutics. Relatively recent refinements in resuscitaand operative measures have themselves tive,
diagnostic,
significantly contributed to improved outcomes.1 A wide variety of anti-infective agents have been mar¬
keted for treatment of patients with intra-abdominal infections, often with marked differences in their anti¬ bacterial spectra, toxic effects, and cost. Guidelines for use of specific agents are not available because of problems in clinical research. Discussions of these problems have been published under the auspices of the Surgical Infection Society.2,3 Most notably, a variety of patient-specific fac¬ tors that are independent of anti-infective therapy affect outcome. These include preexisting medical conditions that may impair adaptive physiologic responses to the ef¬ fects of infection, the patient's resistance to the infection, the source and density of microorganisms, and the sever¬ ity of infection. Guidelines are also not available to aid the physician in making other, more complex therapeutic decisions. This is particularly true in such situations as the presence of uncommon or resistant organisms or apparent failure of the initial operative/antibiotic therapy. In these and other circumstances, insufficient clinical data exist to support
specific therapeutic strategies. This report was developed by the Antimicrobial Agents Committee of the Surgical Infection Society as a set of guidelines for selection of antimicrobial therapy for intraabdominal infections. This guideline is approved by the Executive Council of the Surgical Infection Society. Its purpose is to provide considered guidance to physicians caring for patients with intra-abdominal infection in regard to selection of appropriate anti-infective therapy. SCOPE AND DEFINITION OF INTRA-ABDOMINAL INFECTIONS For this article, intra-abdominal infection and secondary peritonitis are defined as the presence of a purulent exu-
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Table Facultative Cram-negative Bacilli
1.—Microorganisms Included
Facultative
Obligate Anaerobes Bacteroides fragilis
Escherichia coli Klebsiella species
Bacteroides
species species Morganella morganii Other enteric gram-negative species Enterobacter
Table 2.—Conditions That Do Not Require Antibiotic Therapy
Prolonged
Condition
Definition
Early acute appendicitis
Dull-red serosa, edema, induration of appendix As above with subserosal abscess formation; no gangrene, free
suppurative appendicitis
Simple acute cholecystitis Simple
dead bowel
Castroduodenal ulcer
perforation Traumatic enteric
perforations
perforation,
or
periappendiceal
abscess Acute inflammation;
no
perforation, pericholecystic abscess, or cholangitis
Transmural necrosis from
embolie, thrombotic,
or
obstructive vascular occlusion; no established peritonitis or abscess Perforation operated on within 24 h of onset Perforations operated on within 12 h of injury
date in the abdominal cavity derived from an enteric source.2 Intra-abdominal infections are described on the basis of the viscus giving rise to the infecting flora. The sites of origin for infections covered by these guidelines include the following: distal esophagus/stomach/ duodenum; biliary tree; proximal small bowel; distal small bowel; appendix; colon; liver; spleen; and pancreas (in¬ cluding both peripancreatic abscesses and the more un¬ common infected pseudocysts). Postoperative infec¬ tions within the abdomen constitute an important class of intra-abdominal infections. Liver and spleen ab¬ scesses need to be described in relation to cause, eg, secondary to diverticulitis, appendicitis, etc. Intraabdominal infections are then categorized on the basis
of findings at operation or by computed tomography or ultrasound examination as single abscess, multiple ab¬ scesses, and/or
peritonitis. Contiguous infection, such abscess arising in the gallbladder bed, is described as an abscess related to the primary organ site of infection. The bacteria covered by this guideline are detailed in Table 1. We have excluded from further consideration primary peritonitis (infected ascites), infections related to intraperitoneal catheters, extra-abdominal infection. These guidelines do not address conditions in which contami¬ nation has occurred but infection is not established, or conditions in which a largely localized infectious process as a
hepatic
Gram-positive Cocci Enterococci
species Fusobacterium species Clostridium species Peptococcus species Peptostreptococcus species Lactobacillus species
Proteus
Acute
in This Guideline Aerobic
Gram-negative Bacilli Pseudomonas aeruginosa
Staphylococcus species Streptococcus species
is treated by excision (Table 2). In these instances, antibi¬ otic therapy is prophylactic.4"8
PATHOGENESIS AND MICROBIAL CAUSE OF INTRA-ABDOMINAL INFECTION Microorganisms may contaminate the peritoneal cavity due to one or a combination of processes described as traumatic, neoplastic, vascular (ischemie), or inflamma¬ tory. The last category includes such conditions as gastroduodenal perforations due to peptic ulcer disease, Crohn's disease, ulcerative colitis, diverticulitis, intraluminal foreign bodies, peripancreatic infections after acute pancreatitis, appendicitis, and cholecystitis. The microflora encountered in the resulting infections are suffi¬ ciently similar to be grouped together when antimicrobial therapy is considered. Enteric, particularly colonie, sources of infection intro¬ duce hundreds of different bacterial species into the peri¬ toneal cavity, but only a limited number appear to persist at the site of infection. This appears due to different sus¬ ceptibilities to oxygen, serum proteins, and leukocytes and to toxin production. GENERAL ASPECTS OF ANTIMICROBIAL THERAPY IN ABDOMINAL INFECTION It must be clearly stated that the use of antimicrobial agents active against the infecting flora reduces the inci¬ dence of failure.9"11 Antimicrobial therapy may not result in an identifiable improvement in survival rates. The goals of anti-infective therapy are to reduce the incidence of persistent and recurrent intra-abdominal infection. Min¬ imizing drug complications and cost are considerations that should guide selection of agents with similar spectra of activity. In practice, treatment with antimicrobial agents is often begun when the diagnosis of intra-abdominal infection is suspected. This is often before an exact diagnosis is made and before results of appropriate cultures are available. The clinician must, therefore, anticipate the pathogens most likely to be encountered at the site of infection. Intra-abdominal infections require coverage of enteric gram-negative facultative and obligate anaerobic bacilli
(Table 1).
APPROPRIATE SPECIMEN HANDLING Intraoperative cultures are the primary basis for subse¬ quent decisions regarding antimicrobial therapy. Fluid collections, particularly if purulent, should be obtained for Gram's stain and culture. Specimens of infected intraabdominal fluid are either sent to the laboratory in a capped airless syringe with no needle or collected in ap-
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Table 3.—Antimicrobial Sensitivities of Commonly Encountered Pathogens to Parenteral Antibiotics Used in Abdominal Infection* Facultative
Organisms and Aerobes Gram-positive Cocci
Gram-negative
Obligate Anaerobes
Other
Bacilli
Enterococci
Streptococcus Species
0
+ +
+
Penicillin
Gram-negative Gram-positive Gram-positive Bacilli
Bacilli
Cocci
+ + +
+
+ + +
+ + +
Ampicillin Piperacillin
+ + +
+ + +
+
+ + +
+ + +
+ + +
+ + +
+ + +
+ +
+ + +
+ + +
Ticarcillint
+ +
+ +
+ + +
+ +
+ +
+ +
Cefazolin*
+ +
0
+ + +
+
+ + +
+ + +
Cefamandole§ Cefoxitinll
+ +
0
+ + +
+
+ +
+ + +
+ +
0
+ +
+ +
+ + +
+ + +
Cefotaximell
+ + +
0
+ +
+
+ +
+ + +
Imipenem
+ + +
+ +
+ + +
+ + -¬
+ + 4-
+ + -¬
Aztreonam
+ + +
0
0
Aminoglycosides# Clindamycin
+ + -¬
0
0
o
o
o
0
+ -¬
+ + +
+ + +
+ + +
+ + +
+ + +
+ + +
+ + +
+ + +
+ + +
+ + +
+ + +
+ + -¬
Metronidazole
0
0
+ +
+ + +
0
ß-lactamase inhibitorß-lactam combinations
Ampicillin-sulbactam
+ + +
Ticarcillin-clavulanic + + + + + acid + + indicates little or no activity; +, some activity; + + moderate to good tAzlocillin, mezlocillin, and carbenicillin have similar spectra. ilncludes cephalothin, cephapirin, and cephradine. §lncludes cefuroxime, cefonicid, cefotiam, and ceforanide. ¡Includes cefotetan and cefmetazole. Ulncludes ceftriaxone, ceftazidime, cefoperazone, and ceftizoxime. #lncludes gentamicin, tobramycin, netilmicin, and amikacin. ,
propria te separate aerobic and anaerobic transport media. If the Gram's stain reveals a predominance of grampositive cocci, which may indicate that Enterococcus or other fecal streptococci are significant copathogens at the
site of infection, the clinician should consider alterations in the antibiotic regime to include agents specifically ac¬ tive against Enterococcus.12 Appropriate management of Enterococcus is controversial. Some believe that specific anti-Enterococcus therapy should be given only when En¬ terococcus is the only isolate or in the presence of bacter¬ emia. If the Gram's smear reveals gram-negative bacilli, failure to isolate either facultative or obligate anaerobes on culture does not obviate the need to continue to provide
antimicrobial agents pital antimicrobial heeded when initial
against both.
Local or regional hos¬ susceptibility patterns should be empiric therapy is selected.1314
RATIONALE FOR SELECTION OF ANTIBACTERIAL AGENTS In vitro data, especially antimicrobial susceptibility tests, are predictive of the in vivo response of infecting bacteria to particular antibacterial agents. Although a va¬ riety of susceptibility testing techniques are available, disk or automated testing is appropriate for bacteria isolated from intra-abdominal infections except in extraordinary circumstances. Table 3 summarizes the in vitro suscepti¬ bilities of important pathogens to commonly used antiinfective agents in abdominal infection.
activity;
and
+
+, excellent
activity.
The combination of evidence from in vitro data, animal to widespread accep¬ tance of the need to provide empiric antimicrobial therapy directed against Escherichia coli and other common mem¬ bers of the family Enterobacteriaceae and Bacteroides fragijjS 9,i5,i6 Bacteroides fragilis and E coli are the most common isolates from intra-abdominal infections and are the organisms most likely to cause bacteremia in abdominal sepsis, further attesting to their pathogenicity.17 The evidence in support of broadening therapy to cover organisms other than common facultative and obligate anaerobes, such as E coli and fragilis, is more controver¬ sial. Initial empiric coverage of Pseudomonas aeruginosa is associated with a decreased likelihood of persistent or re¬ current abdominal infection if these organisms are iso¬ lated from the site of infection.18 Other clinical trials using anti-infectives not effective against aeruginosa have not found a high incidence of treatment failure with this or¬
studies, and clinical trials has led
ganism.19
ANTIMICROBIAL REGIMENS The recommendations described in these guidelines are based on a variety of factors. These include the in vitro data provided, experience in animal models, documented efficacy in meaningful clinical trials, and certain theoret¬ ical concerns regarding pharmacokinetics, mechanisms of action, and safety profile.
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Table
4.—Acceptable Antimicrobial Regimens
Single Agents Community-acquired infections of mild to moderate severity
Cefoxitin Cefotetan Cefmetazole Ticarcillin-clavulanic acid Severe infections
preferable to the recommended agents listed below. The combination of penicillin or ampicillin plus aminoglyco¬ side plus antianaerobe is recommended only if entero¬ coccal infection is suspected based on Gram's stain or thought to be clinically relevant (eg, associated with en¬ terococcal bacteremia). The choice for a particular patient will depend on the source of infection, the severity of the infection, the pa¬ tient's age, the degree of renal impairment, and local for¬ mulary considerations.
Imipenem-cilastatin Combinations
plus aminoglycosidet (young patient, no hypotension or renal compromise) Antianaerobe* plus third-generation cephalosporini Clindamycin plus monobactam§ *Antianaerobes include clindamycin or metronidazole. tAminoglycosides include gentamicin, tobramycin, netilmicin, Antianaerobe*
and amikacin. iCefotaxime and ceftizoxime. Ceftazidime and ceftriaxone are logical alternatives because of similar antimicrobial properties and lack of adverse effects; clinical data are insufficient.
§Aztreonam.
Not Recommended The following drugs should not be used as empiric therapy unless combined with acceptable agents listed below, because of inadequate coverage of both aerobic and anaerobic organisms: cefazolin and other firstgeneration cephalosporins, penicillin, cloxacillin and
antistaphylococcal penicillins, ampicillin, erythromycin, and vancomycin. Metronidazole and clindamycin should not be used alone because they lack activity against facultative enteric organisms. The following agents should not be used alone because of inadequate coverage of anaerobic gramnegative bacilli: aminoglycosides, aztreonam, polymyxother
ins, cefuroxime, cefonicid, cefamandole,
fotiam, cefotaxime, ceftizoxime, ceftriaxone, and ceftazidime.
ceforanide, cecefoperazone,
Because of inadequate clinical data documenting effi¬ cacy and concerns about resistance, the following drugs should not be used as single agents for empiric therapy despite their relative safety and broad in vitro antibacte¬ rial spectra: piperacillin, mezlocillin, azlocillin, ticarcillin, and carbenicillin. Certain agents have appropriate in vitro spectra of ac¬ tivity but serious toxic effects and are therefore not acceptable. Chloramphenicol is myelosuppressive and may lead to aplastic anemia.20 Moxalactam should not be used because of its potential to cause bleeding.21,22 For patients whose abdominal infection develops in the hospital after previous antibiotic therapy, cefoxitin, cefotetan, cefmetazole, cefotaxime, ceftriaxone, and cefti¬ zoxime should not be used because of the risk of resistant facultative gram-negative organisms. Newer agents, such as quinolones, should not be used until subjected to proper clinical trial.
Recommended Recommended regimens are listed in Table 4. Amino¬ glycosides are associated with the greatest toxic effects, especially in the elderly or patients with renal compro¬ mise, hypotension, and large cumulative dose, and re¬ quire serum level monitoring.2327 Cost or hospital formu¬ lary considerations may make one of these regimens
OTHER CONSIDERATIONS
Safety Antimicrobial agents may cause a wide variety of adverse effects, some of which are not dose related, such as anaphylaxis, and, more commonly, those that are re¬ lated to dose and duration of treatment. Preexisting med¬ ical conditions, such as renal failure and the severity of abdominal infection as manifested by shock, may increase the incidence and severity of drug complications. Com¬ mon, potentially harmful effects of antibacterial agents include immediate hypersensitlvity, nephrotoxic effects, ototoxic effects, coagulopathy, diarrhea, colitis often sec¬ and perhaps fungal superondary to Clostridium infection. Some effects have little potential for harm but may cause discomfort. Others pose diagnostic problems that may in turn prompt unnecessary and even invasive tests to exclude other sources of Clinicians should familiarize themselves with the adverse effects of antimicrobial agents that they use for treatment of intraabdominal infection.
difficile,
difficulty.
Resistance The
of anti-infective agents may result in the development of bacterial resistance. This can take the form of initially susceptible isolates becoming resistant during treatment or the appearance of other organisms resistant to the antimicrobial agents used.28,29 Individual patients may develop extra-abdominal nosocomial infec¬ tions with resistant organisms. An important factor promoting resistance of bacteria to anti-infective agents is the inappropriate use of such agents both inside and outside of hospitals. Indiscrimi¬ nate use must be avoided, and therapy should be contin¬ ued only as long as necessary. Acquisition of resistance during therapy with aminoglycosides is substantially less common than with the penicillins and cephalosporins.30 Therapy with "advanced-generation" penicillins and cephalosporins as single agents is as¬ sociated with the acquisition of resistant strains for Pseudomonas and Enterobacter species.28 If these organisms are identified, an aminoglycoside may be indicated. Drug-resistant organisms, including gram-negative fac¬ ultative bacilli, Enterococcus, Staphylococcus epidermidis, and fungi, are more likely to be encountered in recurrent abdominal infection than in a first episode.31 use
extended-spectrum
Cost
Assuming equivalent efficacy, safety, and potential for
resistance, the least expensive antimicrobial regimen should be chosen over others. The direct costs of drugs may be outweighed by the costs of treatment failure and adverse drug effects.
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Methods of Drug Administration Route.—Intravenous drug administration is routinely used to ensure absorption in patients with hemody¬ namic disturbances. The use of rectal, oral, or intra¬ muscular routes of administration is currently being ex¬ amined as completion therapy, and these routes are attrac¬ tive on the basis of cost. Intraperitoneal antimicrobial instillation, either during or after operation, remains con¬ troversial, with no clear evidence of benefit.32 Dose and Interval. —Recommendations provided in the package insert should be used as guides for deter¬ mining dose and dose interval. Most commonly used antimicrobial agents penetrate peritoneal fluid, and penetration is related to plasma concentrations. The minimum inhibitory concentration is commonly used to describe the activity of a given antibiotic against a particular organism. In this test, the concentration of antibiotic needed to prevent growth of bacteria is mea¬ sured and reported as micrograms per milliliter. Recent work has shown that efficacy of cephalosporins, peni¬ cillins, and other cell-wall-active antibiotics does not depend on the peak serum level but rather on the time during which serum levels are above the minimum inhibitory concentrations of the agent for the bacteria being treated.33-34 This supports the use of more fre¬ quent dosing intervals with lower doses. Because of the relative safety of these drugs, serum concentrations commonly exceed the minimum inhibitory concentra¬ tions for important organisms by several fold. Mini¬ mum inhibitory concentrations determinations are of value in determining antibiotic selection for patients
responding as anticipated. Efficacy of aminoglycoside therapy is related to the rapid achievement of "peak" serum levels four to eight times the anticipated minimum inhibitory concentra¬
not
tions.35 Without serum level monitoring, patients more commonly have subtherapeutic levels rather than toxic levels.36 Current dosing recommendations for amino¬ glycosides include initial dosing at 2 mg/kg for gentamicin, tobramycin, and netilmicin and 20 mg/kg for amikacin, with an initial dosing interval of 12 hours.30 Monitoring of aminoglycoside serum levels is necessary
ensure therapeutic peak levels and nontoxic trough levels. Determination of aminoglycoside peak and se¬ rum levels should be obtained on the first or second dose, and an early change to a therapeutic dose and dosing interval should be made. The common practice of beginning with low doses and adjusting upward results in prolonged delays in achieving therapeutic levels and is associated with an increased incidence of
to
failure.11-37 Duration.—Anti-infective agents are routinely given for 5 to 7 days for generalized peritonitis and localized abdominal abscess. In both categories of infection, an¬ timicrobial agents should be continued until tempera¬ ture and white blood cell count are within normal limits. Discontinuation of anti-infective agents while treatment
patient has fever or leukocytosis is associated with increased risk of recurrent or persistent abdominal infection.38-39 If clinical improvement is not evident within 4 days, or if fever or leukocytosis persists after more than 5 days of therapy, undrained abdominal infection or an inadequately treated extra-abdominal infection should be sought. the an
SPECIAL CONSIDERATIONS
Appendicitis The principles and recommendations for antimicrobial selection in gangrenous and perforated appendicitis and periappendiceal abscesses are as detailed above. The du¬ ration of antimicrobial therapy may be shorter for early acute and acute suppurative appendicitis. In these condi¬ tions, antibacterial treatment is prophylactic and should be begun before the incision to protect the surgical wound from infection. If the appendix is normal, or if it is inflamed but not perforated, the drug or drugs may be discontinued. If gangrene or perforation is found, the anti-infective regimen should be continued until the pa¬ tient has shown clinical improvement with return of bowel function, is afebrile, and has a white blood cell count below 12.0 109/L. Some infections, including diverticulitis without ab¬ scess formation and late appendicitis, may be treated without operation. In this case, antibiotic therapy as de¬ scribed above may be given for hospitalized patients. When a clinical response has been achieved, or if the pa¬ tient is being treated outside the hospital, oral therapy with a combination of agents effective against E coli and ß fragilis may be used. Amoxicillin plus clavulanic acid,
sulfamethoxazole-trimethoprim plus metronidazole, or a quinolone with metronidazole have appropriate in vitro spectra of activity, although no published data on this form of therapy are available.
Septic Complications of Acute Pancreatitis Acute pancreatitis itself may mimic infection with such findings as abdominal pain and tenderness, fever, and leukocytosis. However, the use of prophylactic antimi¬ crobial agents in uninfected acute pancreatitis is not rec¬ ommended. Computed tomography-guided percutane¬ ous aspiration is a reliable and safe method of distinguishing infected from uninfected pancreatitis. The presence of bacteria on Gram's stain or culture of aspi¬ rated material denotes infection. The diagnosis of pancreatic or peripancreatic infection is associated with either necrotic tissue, which requires débridement, or loculated fluid collections, which require drainage. In these circumstances, antimicrobial therapy should be administered as described above, with therapy continued until clinical improvement occurs along with normalized temperature and white blood cell count. There appears to be a risk of acquisition of drugresistant organisms due to superinfection, and cultures should be obtained during each reoperation. Therapy should be guided by results of these cultures. The initial choice of antimicrobial regimen should be based on Gram's stain and culture of infected tissue or fluid taken by percutaneous aspiration or at operation. Ini¬ tial empiric coverage, as in other types of abdominal infection, should include E coli and other aerobes, plus fragilis and other anaerobes. Fungal Peritonitis Candida species may be identified in infected intraabdominal fluid. When fungi are isolated at the first operation for community-acquired intra-abdominal sep¬ sis, therapy with amphoterìcin is not recommended. In patients who have recently received immunosup¬ pressive agents, such as steroids or antineoplastic ther-
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apy,
or
in
patients with recurrent intra-abdominal in¬ is a significant risk of progressive fungal
fection, there
infection if Candida is isolated from intra-abdominal cul¬ tures, and amphoterìcin therapy improves outcome results.40-41
Tertiary or Recurrent Peritonitis In patients with recurrent or persistent abdominal infection, the infecting bacteria may be resistant to anti¬ microbial agents used in initial, empiric therapy.31-42 Treatment must be individualized, depending on previ¬ ous culture reports and local antimicrobial sensitivity patterns. Aminoglycosides may be the agents of choice for any facultative gram-negative organisms identified. Clinical Failure If abdominal infection appears to persist, a focus of in¬ fection that requires drainage is the usual cause. Treat¬ ment failure should be suspected if there is not substan¬ tial resolution of fever, and ileus by the 3rd or 4th postoperative day. The clinical signs of persistent or recurrent abdominal infection may be mimicked by extra-abdominal infection and by a variety of noninfectious processes, including thrombophlebitis and drug fe¬ ver. Persistent or recurrent illness mandates a thorough examination and search for a drainable focus of infection within the abdomen, including noninvasive imaging studies, such as computed tomography or ultrasound ex¬ aminations. If one or more microorganisms isolated at the initial intervention is not susceptible to the antibiotics provided, a change of antimicrobial agents to provide such coverage is indicated. However, rarely will a change in antibiotics effect resolution of persistent or recurrent abdominal sepsis.
leukocytosis,
References DM. Musher Critical importance of early diWD, and treatment of intra-abdominal infection. Arch Surg.
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Thompson JE Jr, Doty JE, Mann LL, Manchester B. Antibiotics in infections of the biliary tract. Surg Gynecol Obstet. 1987;165:285-292. 8. Boey J, Wong J, Ong G. Bacteria and septic complications in patients with perforated duodenal ulcers. Am J Surg.
1982;143:635-639. 9. Lau WY, Fan ST, Yiu TF, Poon GP, Wong SH. Prophylaxis
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metronidazole and cefotaxand double blind trial. Br J
10. Heseltine PNR, Yellin AE, Appleman MD, et al. Perforated and gangrenous appendicitis: an analysis of antibiotic failures. J Infect Dis. 1983;148:322-329. 11. Solomkin JS, Dellinger EP, Christou NV, Busuttil RW. Results of a multicenter trial comparing imipenem/cilastatin to tobramycin/clindamycin for intra-abdominal infections. Ann
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12. Barie PS, Christou NV, Dellinger EP, Rout WR, Stone HH, Waymack JP. Pathogenicity of the enterococcus in surgical infections. Ann Surg. 1990;212:155-159. 13. Thornsberry C. Review of in vitro activity of third\x=req-\ generation cephalosporins and other newer beta-lactam antibiotics against clinically important bacteria. Am J Med.
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14. Cornick NA, Cuchural GJ Jr, Snydman DR, et al. The antimicrobial susceptibility patterns of the Bacteroides fragilis group in the United States, 1987. J Antimicrob Chemother.
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15. Bartlett JG, Onderdonk AB, Louie T, Kasper DL, Gorbach SL. A review: lessons from an animal model of intra-abdominal sepsis. Arch Surg. 1978;113:853-857. 16. Clarke JS, Condon RE, Bartlett JG, Nichols RL, Ochi S. Preoperative oral antibiotics reduce septic complications of colon operations: results of a prospective, randomized, double-blind clinical study. Ann Surg. 1977;186:251-259. 17. Lorber B, Swenson RM. The bacteriology of intra\x=req-\ abdominal infections. Surg Clin North Am. 1975;55:1349-1354. 18. Yellin AE, Heseltine PN, Berne TV, Appleman MD, Gill MA, Riggio CE, Chenella FC. The role of Pseudomonas species in patients treated with ampicillin and sulbactam for gangrenous and perforated appendicitis. Surg Gynecol Obstet.
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Med Clin North Am. 1990;74:1059-1076. S, Bergeron MG. Pathogenic factors in aminoglycoside-induced nephrotoxicity. Toxicol Lett. 1990; ure.
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care
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32. Schein M, Saadia R, Decker G. Intraoperative peritoneal lavage. Surg Gynecol Obstet. 1988;166:187-195. 33. Leggett JE, Fantin B, Ebert S, et al. Comparative antibiotic dose-effect relations at several dosing intervals in murine pneumonitis and thigh-infection models. J Infect Dis. 1989;
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audit of
aminoglycoside
Invited This is a well-thought-out position paper providing sound advice about choosing among the surfeit of antibiotics cur¬ rently available to treat patients with infections in the abdo¬ men. It also provides an important message about a matter once controversial but no longer in dispute: the spectrum of antibiotics chosen must cover both aerobes and anaerobes to achieve success. The treatment of intra-abdominal infections encompasses some still-controversial issues about which experts differ. Even though I chaired the Executive Committee of the Sur¬ gical Infection Society at the time the society approved this position paper, there are some points in this report to which I would take exception. Let me first emphasize that the pa¬ per contains very solid advice that, if followed, will help cure suffering intra-abdominal infection. Having said patients that, let me illustrate the nature of my exceptions by discuss¬ ing two points: the role of Enterococcus in abdominal infection and apparent differences in efficacy against E coli between ß-lactamase inhibitor antibiotic combinations. Even though ignored in this paper, the pathogenic role of Enterococcus in a polymicrobic abdominal infection continues to be a matter of controversy. Controversy arises because En¬ terococcus is not a vigorous pathogen; it has comparatively poor capacity to invade and persist in tissue. Enterococci do not produce toxins or destructive enzymes, as do other gram-positive organisms, and they lack the capacity to exclude other bacteria actively from their environment as, for Rather, Enterococcus is a sur¬ example, E coli does so vivor organism, often persisting because it is widely resistant to many antibiotics. When considering the pathogenic role of Enterococcus, it is important to distinguish between monomicrobic and poly¬ microbic infections. In monomicrobic situations, such as bac¬ terial endocarditis, in which Enterococcus is the only organism recovered, it clearly is acting as a pathogen and requires pri¬ mary treatment. However, in the context of abdominal infec¬ tions that are polymicrobic in nature, and in which Enterococ¬ cus is only one of many species of bacteria present, it rarely acts as a primary pathogen. However, enterococci will persist if initial treatment of the infection fails. When such a clinical course is predictable, as in immunocompromised patients, then coverage of Enterococcus as a part of initial therapy is reasonable. But, for most patients, antibiotic therapy cover¬ ing enterococci in intra-abdominal infections is not necessary,
readily.
glycoside plasma
levels with therapeutic outcome in gram\x=req-\ Am J Med. 1984;77:657-662. 38. Lennard ES, Dellinger EP, Wertz MJ, Minshew BH. Implications of leukocytosis and fever at conclusion of antibiotic therapy for intra-abdominal sepsis. Ann Surg.
negative pneumonia.
1982;195:19-24. 39. Lennard ES, Minshew BH, Dellinger EP, Wertz M. Leuko-
cytosis at termination of antibiotic therapy: its importance for intra-abdominal sepsis. Arch Surg. 1980;115:918-921. 40. Solomkin
JS, FlohrA, Simmons RL. Candida infections in
surgical patients:
dose requirements and toxicity of amphotericin B. Ann Surg. 1982;195:177-185. 41. Solomkin JS, Flohr AB, Quie PG, Simmons RL. The role of Candida in intraperitoneal infections. Surgery. 1980;88:524\x=req-\ 530. 42. Walsh GL, Chiasson P, Hedderich G, Wexler MJ, Meakins JL. The open abdomen: the Marlex mesh and zipper technique: a method of managing intraperitoneal infection. Surg Clin North Am. 1988;68:25-40.
Commentary nor
is the addition of antienterococcal coverage needed if ini¬
peritoneal cultures yield enterococci but the patient clin¬ ically is doing well.1 My second quibble concerns the recommendation of ticarcillin-clavulanic acid in preference to ampicillintial
sulbactam, based
on the apparent resistance of some strains of E coli to ampicillin-sulbactam. It is increasingly apparent that the difference in coliform sensitivity to these drugs is in¬ fluenced by the methods used to measure sensitivity and re¬ sistance in the laboratory. The disks used to measure the ef¬ ficacy of these antibiotics are not identical; the ticarcillinclavulanic acid disk contains 75 µg of ticarcillin, whereas the ampicillin-sulbactam disk contains 10 µg of ampicillin. The difference in functional antibiotic concentration has the potential to alter apparent sensitivity (false resistance) when the efficacy of the two drug combinations is compared. Were it not for the artifactual deficit in efficacy against coliforms, ampicillin-sulbactam theoretically would be preferred be¬ cause it is more active against staphylococci, the sulbactam component is an active antibiotic in its own right (although a weak one), and sulbactam does not compete for penicillinbinding sites as does clavulanic acid. In fact, both drugs are equally efficacious in treating abdominal infections, and the differences between them are clinically unimportant. There¬ fore, I would appropriately update the information contained in Table 3 and broaden the recommendations contained in Table 4. My comments are offered primarily so that readers will be aware that, as is true of most clinical situations, all is¬ sues are not totally settled. Optimal therapy will change in evolutionary ways as new information about bacterial patho¬ genesis and antibiotic efficacy is acquired. It continues to be important for physicians to keep current with the new infor¬ mation continuously available in the literature. This Surgical Infection Society position paper provides a solid base on which to build a future framework of knowledge. Robert E. Condon, MD, MS Milwaukee, Wis
Reference 1. Barie
PS, Christou NV, Dellinger EP, Rout WR, Stone HH, Waymack JP. Pathogenicity of the Enterococcus in surgical infections. Ann Surg. 1990;212:155-159.
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