Duration of Antimicrobial Therapy in Treating Complicated Intra-Abdominal Infections: A Comprehensive Review

Abstract

Background:

Surgeons managing intra-abdominal infections should always respect the basic principles of antibiotic treatment. An adequate duration of antimicrobial therapy is important to optimize empiric therapy and minimize selective pressures favoring antimicrobial resistance.

Methods:

The optimal duration of antibiotic therapy for intra-abdominal infections (IAIs) has been debated in the last years. A literature research, based on PubMed database and limited to English language publications, was performed without restriction of time or type of manuscript.

Results:

In stable patients a short course of antimicrobial therapy (3–5 d) after adequate source control, depending on fever and leukocytosis, may be a reasonable option. In critically ill patients with severe sepsis and septic shock, an individualized approach is always mandatory and patient's inflammatory response should be monitored regularly. Procalcitonin may be helpful for guiding antibiotic treatment in critically ill surgical patients and in predicting treatment response.

Conclusions:

General surgeons managing intra-abdominal infections should always respect the basic principles of antibiotic treatment. Duration of antimicrobial treatment is an important variable to evaluate in treating complicated intra-abdominal infections.

General surgeons managing intra-abdominal infections should always respect the basic principles of antibiotic treatment [1]. In order to minimize the risk of antimicrobial resistance and optimise treatment outcome, it is important to select an appropriate antibiotic (to cover likely pathogens basis on local epidemiological data and guidelines), prescribe at an appropriate dose and for the appropriate duration. Antimicrobial resistance has become a substantial global health issue and efforts to potentially reduce the risk [2], while not compromising individual patient care, are not well known to general surgeons. This review focuses on the evidence base surrounding the duration of antibiotic therapy for complex intra-abdominal sepsis.

The optimal duration of antibiotic therapy for intra-abdominal infections (IAIs) has been extensively debated. A universally accepted classification divides intra-abdominal infections into complicated and uncomplicated [3]. In the event of uncomplicated IAIs, where the infection only involves a single organ and does not extend to the peritoneum and when source of infection is treated effectively by surgical excision, perioperative prophylaxis is sufficient. For example, in the setting of uncomplicated acute cholecystitis and acute appendicitis it has been well demonstrated that antibiotic pre-operative prophylaxis reduces infectious complications and single doses have the same impact of multiple doses [4 –6]. Whereas, in the event of complicated IAIs (cIAIs) the infectious process proceeds beyond the organ, causing either localized or diffuse peritonitis. Treatment of patients with cIAIs involves generally both source control and antibiotic therapy. Antibiotics in treating cIAIs can prevent local and hematogenous spread and may reduce late complications. More recently, it has been suggested that when source control is adequate, a shorter course of antibiotics should be sufficient for curing, could decrease the risk of antimicrobial resistance and adverse effects.

Hypothesizing that a longer duration of antimicrobial therapy for management of intra-abdominal infections could be associated with an increased risk of extra-abdominal infections (EAI) and high mortality, Riccio et al. [7] reviewed all intra-abdominal infections occurring in a single institution between 1997 and 2010. Patients with IAI who developed a subsequent EAI were compared with those who did not develop an EAI. Among 2,552 patients with IAI, 549 (21.5%) were followed by EAI. Intra-abdominal infections that were followed by EAI were associated with a longer initial duration of antimicrobial therapy than were IAI without subsequent EAI. Guidelines by Surgical Infection Society (SIS) and Infectious Diseases Society of America (IDSA) published in 2010 [8], recommend a treatment course of 4 to 7 d, depending on the clinical response. World Society of Emergency Surgery (WSES) guidelines published in 2013 [9] recommend to shorten antimicrobial therapy for patients demonstrating a positive response to treatment, if there are no signs of persistent leukocytosis or fever.

Despite these recommendation, observational studies show that therapy is typically administered for longer periods. For example, in 2014 data from the CIAOW study (Complicated intra-abdominal infections observational study) showed that the mean duration of antimicrobial therapy was 11.1 d [10]. This study described the epidemiological, clinical, and treatment profiles of complicated intra-abdominal infections in a worldwide context.

Duration of Antimicrobial Therapy in Treating Complicated Intra-Abdominal Infections

It is well known that in setting of uncomplicated intra-abdominal infections such as acute appendicitis and acute cholecystitis when the focus of infection is controlled by surgery, it can be treated without post-operative antibiotics. A multi-center French non inferiority randomized clinical trial including 414 patients treated for grade I or II acute calculous cholecystitis and who received 2 g of amoxicillin plus clavulanic acid three times a day, and once at the time of surgery, was published recently [11]. Among patients with mild or moderate calculous cholecystitis who received pre-operative and intra-operative antibiotics, lack of post-operative treatment with amoxicillin plus clavulanic acid did not result in a greater incidence of post-operative infections. A randomized controlled trial [12] of 269 patients aged 15–70 y with non-perforated appendicitis undergoing open appendectomy was published in 2005. Ninety-two patients received single dose pre-operative (group A), 94 received three-dose (group B), and 83 received 5-d perioperative (group C) regimens of cefuroxime and metronidazole. The rate of post-operative infective complication was not substantially different among the groups (6.5% group A, 6.4% group B, 3.6% group C). The duration of antibiotic therapy had no substantial effect on the length of hospital stay. Complications related to antibiotic treatment were substantially more common for 5-d perioperative antibiotic group (C) compared with single dose pre-operative antibiotic group (A) (p = 0.048).

In the case of cIAIs, duration of antimicrobial therapy is based on the clinical response of the patient to the treatment.

In the early 1980s, two studies from Lennard et al. demonstrated a correlation existing between fever and leukocytosis at the time of antibiotic cessation and treatment failure [13,14].

From the 1990s, the results of retrospective studies on the effect of an abbreviated course of antimicrobial therapy have been published. In 1994 Schein et al. [15] published a study on 163 patients in having emergency abdominal surgery where antibiotic duration was modified based on the degree of contamination and infection found intra-abdominally. Twenty-three of these consecutive patients with diffuse peritonitis were assigned to receive 3 to 5 d of antibiotics.

In 2000 Taylor et al. [16] published a small, randomized trial involving 94 patients with complicated appendicitis. In all enrolled patients, antibiotics were discontinued after resolution of clinical signs of infection; however, in the first group, patients were given a minimum of 5 d of antibiotics, whereas in the second group patients had no minimum defined duration of treatment. The first group received an average of 5.9 d of antibiotic treatment, whereas the second group received an average of 4.3 d of treatment. Infectious complications were not statistically different between the two groups (13.0% in the first and 12.5% in the second group). Average hospital stay was also not statistically different between the two groups. These data suggested that a fixed duration of therapy may lead to a needless longer treatment with no apparent improvement in the outcomes.

Hedrick et al. in 2007 retrospectively analyzed [17] the relation between the duration of antibiotic therapy and infectious complications. Shorter courses of antibiotics were associated with similar or fewer complications than prolonged therapy. The authors concluded that, adopting a tactic of a fixed duration of therapy, rather than basing duration on resolution of fever or leukocytosis, appeared to yield similar outcomes with less antibiotic use.

A double-blind, multi-center, randomized clinical study, published in 2008 [18], compared the clinical and bacteriological efficacy and tolerability of ertapenem (1 g/d) 3 d (group I) vs >or = 5 d (group II) in 111 patients with localized peritonitis of mild to moderate severity, requiring surgical intervention. In patients with localized community-acquired intra-abdominal infection, a 3-d course of ertapenem had the same clinical and bacteriological efficacy as a standard duration.

In the setting of complicated acute appendicitis an observational cohort study of adult patients was published in 2014 [19]. Out of a total of 1143 patients with acute appendicitis who underwent appendectomy, 267 (23.4 percent) had complicated appendicitis. The duration of post-operative antimicrobial therapy was 3 d in 135 patients (50.6 percent) and at least 5 d in 123 (46.1 percent). No difference was found between antibiotic treatment for 3 or 5 d in terms of developing an intra-abdominal abscess (odds ratio (OR) 1.77, 95 percent confidence interval 0.68 to 4.58; p = 0.242) or a surgical site infection (OR 2.74, 0.54 to 13.80; p = 0.223).

Recently a randomized study on appropriate duration of antimicrobial therapy was published [20]. The study randomized 518 patients with cIAIs and adequate source control to receive antibiotics until 2 d after the resolution of fever, leukocytosis, and ileus, with a maximum of 10 d of therapy (control group), or to receive a fixed course of antibiotics (experimental group) for 4 ± 1 calendar days. Complications such as surgical-site infection, recurrent intra-abdominal infection, or death occurred in 56 of 257 patients in the experimental group (21.8%), as compared with 58 of 260 patients in the control group (22.3%) (absolute difference, −0.5 percentage point; 95% confidence interval [CI], −7.0 to 8.0; p = 0.92). The median duration of antibiotic therapy was 4.0 d (interquartile range, 4.0 to 5.0) in the experimental group, as compared with 8.0 d (interquartile range, 5.0 to 10.0) in the control group (absolute difference, −4.0 d; 95% CI, −4.7 to −3.3; p < 0.001). No substantial differences between the two groups were found in the individual rates of the components of the primary outcome or in other secondary outcomes. However, in the study, 18% of patients in the experimental group did not adhere to the protocol and received a treatment course that was longer than the duration specified. The authors concluded that in patients with cIAIS undergoing an adequate source-control procedure, the outcomes after approximately 4 d fixed-duration antibiotic therapy were similar to those after a longer course of antibiotics that extended until after the resolution of physiological abnormalities.

Although in stable patients a short course of antimicrobial therapy (3–5 d) after adequate source control, depending on fever and leukocytosis, may be reasonable, some patients with abdominal sepsis leading to severe sepsis may present a more complex and unpredictable clinical course; therefore, in those patients an individualized approach is always mandatory and inflammatory response should be monitored regularly. Patients who have signs of sepsis beyond 5 to 7 d of antibiotic treatment warrant aggressive diagnostic investigation to determine an ongoing uncontrolled source of infection or reasons for antimicrobial treatment failure.

It is well known that sepsis is a multi-factorial syndrome that may evolve into conditions of variable severity [21]. The risk factors for organ failure include the causative organism and the patient's genetic composition, underlying health status, and pre-existing organ function [22]. There are well known risk factors that most commonly may precipitate severe sepsis, including advanced age, acquired immunodeficiency syndrome, and use of immunosuppressive agents [22]. The high mortality still associated with sepsis, requires to maintain a high index of clinical suspicion in patients leading to severe sepsis and septic shock. These patients should always be monitored carefully with inflammatory response markers. The most widely studied biomarkers in clinical settings are the acute phase proteins (CRP) and procalcitonin (PCT).

CRP measurement is cheap and rapidly available, but increases in CRP concentrations are non-specific, because they can be observed, i.e., after surgery or trauma and are not specific to bacterial infection [23]. Most recently, procalcitonin (PCT) has been suggested as a novel biomarker that may be useful in guiding therapeutic decision making in the management of sepsis. It may be a helpful tool in determining the timing and appropriateness of escalation of antimicrobial therapy in sepsis [24].

Currently, procalcitonin (PCT) has emerged as a laboratory variable allowing early differentiation between SIRS and sepsis [25] and it has recently been used to guide antibiotic treatment in critically ill patients and predict treatment response [26].

Hochreiter et al. published in 2009 [27] a prospective trial to value the role of procalcitonin for guiding antibiotic therapy in surgical intensive care patients. All patients requiring antibiotic therapy based on confirmed or highly suspected bacterial infections and at least two concomitant systemic inflammatory response syndrome criteria were eligible. One hundred ten surgical intensive care patients receiving antibiotic therapy after confirmed or high-grade suspected infections were randomly assigned to either a PCT-guided (study group) or a standard (control group) antibiotic regimen. In 57 patients antibiotic therapy was guided by daily PCT and clinical assessment and adjusted accordingly. The control group comprised 53 patients with a standardized duration of antibiotic therapy over 8 d. In the PCT group the duration of antibiotic therapy was substantially shorter than in the control group without negative effects on clinical outcome. The authors concluded that monitoring of PCT is a helpful tool for guiding antibiotic treatment in surgical intensive care patients. This may contribute to an optimized antibiotic regimen with beneficial effects on microbial resistance and costs.

To investigate whether a PCT-based algorithm could safely reduce antibiotic exposure patients with secondary peritonitis a prospective was published in 2014 [28]. From April 2012 to March 2013, patients diagnosed at the emergency department with secondary peritonitis and underwent emergency surgery were enrolled. PCT concentrations were obtained pre-operatively, on post-operative days 1, 3, 5, and 7, and on subsequent days if needed. Antibiotics were discontinued if PCT was <1.0 ng/mL or decreased by 80% versus day 1, with resolution of clinical signs. The median duration of antibiotic exposure in PCT group was 3.4 d (interquartile range [IQR] 2.2 d), whereas 6.1 d (IQR 3.2 d) in the control group (p < 0.001). The PCT algorithm substantially improves time to antibiotic discontinuation (p < 0.001, log-rank test). The rates of adverse events were comparable between two groups. A multivariable adjustment using an extended Cox model demonstrated that the PCT-based algorithm was substantially associated with a 87% reduction in hazard of antibiotic exposure within 7 d (hazard ratio [HR] 0.13, 95% CI 0.07–0.21, p < 0.001), and a 68% reduction in hazard after 7 d (adjusted HR 0.32, 95% CI 0.11-0.99, p = 0.047).

More recently a multi-center retrospective study [29] including patients with secondary peritonitis, requiring surgery, and at least 48-h SICU admission was published to assess if procalcitonin-guided therapy may reduce length of antibiotic treatment in intensive care unit. A total of 121 patients (52 PCT-guided, 69 non-PCT-guided) admitted from June 2012 to June 2013 were enrolled in the study. Length of intra-SICU (median, 5.0 d; both groups) or in-hospital (median, 20.0 vs 17.5 d) stay, and mortality intra-SICU (9.6% vs 13.0%), 28-d (15.4% vs 20.3%), or in-hospital (19.2% vs 29.0%) were not substantially different (PCT-guided vs. non-PCT-guided). Antimicrobial therapy was shorter in the PCT-guided group (5.1 ± 2.1 vs 10.2 ± 3.7 d, p < .001), without differences between patients with and without septic shock.

Conclusions

Surgeons managing intra-abdominal infections should always respect some basic principles of antibiotic treatment. The timing, regimen, dose, route of administration should be always optimized in planning empiric treatment. However, duration of treatment is also an important variable to be evaluated. An insufficient duration of antimicrobial regimen may be most strongly associated with unfavorable outcomes. On the other hand excessive duration of antimicrobial use may contribute to the emergence and spread of drug-resistant micro organisms. The classification of intra-abdominal infections in complicated versus uncomplicated is still useful because it can differentiate patients needing antimicrobial prophylaxis and patients needing antimicrobial therapy. Complicated IAIs are still an important cause of morbidity and are frequently associated with poor prognosis and need an adequate and appropriate source control and antimicrobial treatment. Whereas in stable patients a short course of antimicrobial therapy (3–5 d), depending on the fever and leukocytosis, may be a reasonable option after adequate source control, in critically ill patients with severe sepsis and septic shock an individualized approach is mandatory and patient's inflammatory response should be monitored steadily.

Footnotes

Author Disclosure Statement

No competing financial interests exist.

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