Optimizing antibiotics in patients with intra-abdominal infections

A simple and universally accepted classification divides inytra-abdominal infections (IAIs) into complicated and uncomplicated.

In the event of uncomplicated IAIs, the infection only involves a single organ and does not extend to the peritoneum. When the focus of infection is controlled by surgical excision, post-operative antibiotic therapy is not necessary.

In the event of complicated IAIs (cIAIs), the infectious process proceeds beyond the organ into the peritoneum, causing either localized or diffuse peritonitis. Treatment of patients with cIAIs involves generally both source control, antibiotic therapy, and potentially novel therapies targeted at modulating or ameliorating the host inflammatory response.

Antibiotic selection

Initial antibiotic therapy for patients with cIAIs is typically empirical.  A patient with abdominal sepsis needs immediate treatment, and microbiological data (culture and susceptibility results) can require up to 48–72 h before they are available for a more detailed analysis. Selection of appropriate empiric antibiotic therapy is critical for preventing unnecessary morbidity and mortality from cIAIs. Empirical antimicrobial therapy should be based on:

  1. local epidemiology,
  2. individual patient risk factors for multidrug resistant organisms (MDROs),
  3. clinical severity.

Local epidemiology

Knowledge of local rates of resistance and the risk factors that suggest MDROs should be involved as essential components of the clinical decision-making process when deciding on which antimicrobial regimen to use for empiric treatment of infection. Every clinician starting empiric therapy should know the local epidemiology. Surveillance initiatives are important, both in a local and in a global context.

Individual patient risk factors for MDROs

Predicting the pathogens and potential resistance patterns of a given infection begins by establishing whether the infection is community-acquired (CA-IAIs) or hospital-acquired (HA-IAIs). For patients with CA-IAIs, agents with a narrower spectrum of activity are preferred. However, in CA-IAI patients at risk for extended-spectrum beta-lactamases (ESBLs) producing Enterobacteriaceae infections, anti-ESBL-producer coverage may be warranted. For patients with HA-IAIs, antibiotic regimens with broader spectra of activity are preferred.

The major pathogens involved in CA-IAIs are usual residents of gastrointestinal flora, including Enterobacteriaceae, streptococci, and certain anaerobes (particularly Bacteroides fragilis). Narrower spectrum antimicrobial agents are appropriate for these patients.

In the context of IAIs, the main resistance problem is posed by ESBL-producing Enterobacteriaceae, which are prevalent in HA-IAIs but observed in CA-IAIs too. Specific risk factors for ESBL-producing bacteria in CA-IAIs include recent exposure to antibiotics (particularly third generation cephalosporins or fluoroquinolones) within 90 days or known colonization with ESBL producing Enterobacteriaceae.

Although increasing overtime everywhere, carriage of ESBL producing Enterobacteriaceae did not evolve with the same dynamics and large intra- and inter-regional variations have been observed. Poor access to drinking water, water pollution, and a high population density are efficient drivers for ESBL producing Enterobacteriaceae dissemination, as for any fecally-orally transmitted diseases.

By contrast, for patients with HA-IAI, antimicrobial regimens with broader spectra of activity are preferable, as those patients have a higher risk of infections due to MDROs.

During the past 2 decades the incidence of HA-IAIs caused by resistant microorganisms has significantly risen, probably in relationship with high level of antibiotic exposure and increasing rate of patients with one or more predisposing conditions such as recent exposure to antibiotics, high severity of illness, advanced age, co-morbidity, degree of organ dysfunction, low albumin level, poor nutritional status, immunodepression and presence of malignancy.

The inevitably increased carbapenem consumption has been associated to increasing carbapenem-resistant Enterobacteriaceae. The rapid spread of carbapenem-resistant Klebsiella pneumoniae is now an additional major threat for antimicrobial therapy in hospitals worldwide, and stresses the concept that the use of carbapenems must be mandatorily optimized in terms of indication and exposure. In the context of an appropriate antimicrobial stewardship, carbapenem sparing treatment should be always recommended particularly in the settings where there is a high incidence of carbapenem resistant K. pneumoniae.

Clinical severity

Infections are among the main factors contributing to mortality in intensive care units (ICU). Abdominal sepsis is a common indication for admission to the ICU. The abdomen is the second most common site of invasive infection among critically ill patients.

The choice of the antimicrobial regimen poses serious problems for the management of critically ill patients. In critically ill patients an early correct empirical antimicrobial therapy has a significant impact on the outcome, independently by the site of infection, and an inadequate empiric antimicrobial regimen is associated with unfavorable outcomes in critical ill patients. In these patients the following strategies should be always implemented to obtain an optimal response to therapy:

  • early source control procedures when indicated,
  • early initiation of therapy (ideally, within 1 h),
  • correct dosing,
  • considering risk factor for MDRO.

In these patients to ensure timely and effective administration of antibiotics, clinicians should always consider the pathophysiological status of the patient as well as the pharmacokinetic properties of the employed antibiotics. The correct dose and correct administration of antimicrobials should always include:

  1. loading dose when indicated, especially in critically ill patients,
  2. extended or prolonged infusion for beta-lactam antibiotics,
  3. peritoneal distribution.

Intra-operative specimens

Although a lack of impact on patient outcomes by bacteriological cultures has been documented in patients with community-acquired IAI, especially in appendicitis, the results of microbiological testing may have great importance for the choice of therapeutic strategy of every patient, in particular, in the adaptation of targeted antimicrobial treatment in patients at risk of unpredictable organisms or in critically ill patients.

Obtaining microbiological results from intra-operative culture from the site of infection has two advantages: (a) to expand antimicrobial regimen if the initial choice was too narrow and (b) to perform de-escalation of antimicrobial therapy if the empirical regimen was too broad.

Intraperitoneal specimens for microbiological evaluation from the site of infection are always recommended for patients with HA-IAIs or with CA-IAIs at risk for resistant pathogens (previous antimicrobial therapy) and in critically ill patients.

Duration

In the event of uncomplicated IAIs, the infection involves a single organ and does not extend to the peritoneum. When the source of infection is treated effectively by surgical excision, post-operative antimicrobial therapy is not necessary, as demonstrated in managing uncomplicated acute appendicitis or cholecystitis. In complicated IAI, the infectious process extends beyond the organ, causing either localized or diffuse peritonitis (examples include: perforated appendicitis, perforated peptic ulcer, perforated diverticulitis, and post-operative anastomotic leaks). Treatment of patients with complicated IAI generally involves both source control and antibiotic therapy. Antibiotics to treat patients with IAIs can prevent local and hematogenous spread and may reduce late complications.

In patients with IAIs, when patients are not severely ill and when source control is complete, a short course (3–5 days) of post-operative therapy is suggested. Patients who have signs of sepsis beyond 5 to 7 days of treatment warrant aggressive diagnostic investigation to determine if an ongoing uncontrolled source of infection. In patients with ongoing peritonitis relaparotomy may be necessary.

The high mortality associated with abdominal sepsis requires clinicians to maintain a high index of clinical suspicion of treatment failure and the early diagnosis of ongoing infections. These patients should always be monitored carefully including the potential use of inflammatory response markers.

The most studied biomarkers in clinical settings are the acute phase proteins (CRP) and procalcitonin (PCT).

Recently, 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 to determine the timing and appropriateness of escalation of antimicrobial therapy in sepsis.

Antibiotic armamentarium

IAI may be managed by either single or multiple antimicrobial regimens.

Beta-lactam/beta-lactamase inhibitor combinations (BLBLI), including amoxicillin/clavulanate and piperacillin/tazobactam, have an in vitro activity against Gram-positive, Gram-negative and anaerobe organisms. Amoxicillin/clavulanate  is still an acceptable option for the treatment of  mild CA-IAIs. However increasing antimicrobial resistance to amoxicillin/clavulanate among E. coli and other Enterobacteriaceae in community-acquired isolates, has compromised clinical utility of this agent for empirical therapy of serious Gram-negative infections. Broad-spectrum activity of piperacillin/tazobactam, including anti-pseudomonal, anti-enterococcal and anaerobic coverage, still make it an attractive option in the management of severe IAIs. The use of piperacillin/tazobactam in ESBLs infections is still controversial.

Most isolates of E. coli and other Enterobacteriaceae remain susceptible to third-generation cephalosporins. Among this drug class, cefotaxime, ceftriaxone and ceftizoxime, in combination with metronidazole may be options for empirical therapy of CA-IAI, due to the relatively narrow spectrum of coverage bacause these agents lack activity against P. aeruginosa. On the other hand, ceftazidime and cefoperazone have activity against P. aeruginosa, but have relatively less activity against streptococci as compared to other third-generation cephalosporins. Cefepime, a fourth-generation cephalosporin, with broader spectrum activity compared to ceftriaxone is a poor inducer of AmpC beta-lactamase, and is poorly hydrolyzed by the enzyme, allowing it to be effective against AmpC-producing organisms.

Fluoroquinolones (FQ) have been widely used in the treatment of intra-abdominal infections because of their excellent activity against aerobic Gram-negative bacteria and tissue penetration. Ciprofloxacin has in vitro activity against P. aeruginosa.  Except for moxifloxacin, the FQ have a very moderate activity against anaerobes and have been used in combination with metronidazole in the empiric treatment of IAI. The worldwide increase in FQ resistance among E. coli and other Enterobacteriaceasaee has limited the non-stratified use of FQ for empirical treatment of patients with IAI, particularly in critically-ill patients and those with HA-IAI.

For decades, carbapenems have been the antibiotics of first choice for ESBLs. The best option for targeting ESBLs (though with no coverage of P. aeruginosa) is ertapenem, a once daily administered carbapenem that otherwise shares the activity of imipenem, meropenem and doripenem against most species, including ESBL producing pathogens. Imipenem/cilastatin, meropenem and doripenem provide coverage for Gram-negative non-fermenting bacteria (e.g. P. aeruginosa and A. baumannii). However, inappropriate use of carbapenems should be avoided because there is an association with the increase in carbapenem-resistant Enterobacteriaceae,

Other options include aminoglycosides, particularly for suspected infections by Gram negative bacteria, and tigecycline especially when MDRO are suspected, though caution is advised for the latter, in the situation of a bacteremia. Tigecycline, an antibiotic from the group of the tetracyclines, does not feature in vitro activity against P. aeruginosa or certain Enterobacteriaceae (Proteus spp., Serratia spp., Morganella morganii, Providencia stuartii). However, it remains a viable treatment option for patients with cIAIs due to its favorable in vitro activity against anaerobic organisms, enterococci, several ESBLs and some strains of carbapenemase-producing Enterobacteriaceae. Because of poor plasma concentration tigecycline performs poorly in bacteremic patients.  Tigecycline should not be considered first line for health care associated pneumonia and bacteremia. Nonetheless, tigecycline remains an important treatment option for patients with complicated IAI.

Recent challenges in the management of multi-drug resistant Gram-negative infections, especially in critically ill patients, have reviewed the use of “old” antibiotics, such as polymyxins and fosfomycin.

Ceftolozone/tazobactam and ceftazidime/avibactam are new antibiotics that have been approved for treatment of cIAIs (in combination with metronidazole). By adding beta-lactamase inhibitor (tazobactam or avibactam), these new agents have strong activity against MDR Gram-negative pathogens. Unlike other beta-lactam and beta-lactamase inhibitor combination agents, these new agents should be combined with metronidazole for complicated IAI due to limited activity against some Bacteroides species. These antibiotics will be valuable for treating infections caused by MDR Gram-negative bacteria in order to preserve carbapenems. Ceftazidime/avibactam has demonstrated consistent activity against KPC-producing organisms. Cautious clinical use is advised, until their precise roles are further defined as empirical treatment.

Suggested regimens

Empiric antibiotic regimens for non-critically ill patients with community-acquired IAIs. Normal renal function

 

Community-acquired cIAIs

Non-critically ill patients

Amoxicillin/clavulanate 1.2-2.2 g 8-hourly

or

Ceftriazone 2 g 24-hourly + Metronidazole 500 mg 6-hourly

or

Cefotaxime 2g 8-hourly + Metronidazole 500 mg 6-hourly

or

In patients with beta-lactam allergy

Ciprofloxacin 400 mg 12-hourly + Metronidazole 500 mg 6- hourly

or

Moxifloxacin 400 24-hourly

or

In patients at high risk for infection with community-acquired ESBL-producing Enterobacteriacea

Ertapenem 1 g 24 hourly

or

Tigecycline 100 mg initial dose, then 50 mg 12-hourly

Empiric antibiotic regimens for critically ill  patients with community-acquired IAIs. Normal renal function

Community-acquired IAIs

Critically ill patients

Piperacillin/Tazobactam 4.5 g 6-hourly

or

In patients at high risk for infection with community-acquired ESBL-producing Enterobacteriacea if source control is not effective

Meropenem 1 g 8-hourly

or

Doripenem 500 mg 8-hourly

or

Imipenem/Cilastatin 1 g 8-hourly

Empirical coverage of Enterococci is not generally recommended for patients with community-acquired IAIs. However in critically ill patients at high risk for infection with Enterococci including immunocompromised patients or patients with recent antibiotic exposure consider use of Ampicillin 2 g 8-hourly if the patients are not being treated with piperacillin/tazobactam or imipenem/cilastatin (active against ampicillin-susceptible enterococci)

In patients with documented beta-lactam allergy consider use of antibiotic combinations with Amikacin 15–20 mg/kg 24-hourly.

 

Empiric antimicrobial regimens for non-critically ill patients with healthcare-associated IAIs. Normal renal function

Healthcare-associated IAIs

Non-critically ill patients

Piperacillin/Tazobactam 4.5 g 6-hourly

or

In patients at higher risk for infection with MDROs including recent antibiotic exposure, patient living in a nursing home or long-stay care with an indwelling catheter, or post-operative IAI if source control is not effective

Meropenem 1 g 8-hourly

or

Doripenem 500 mg 8-hourly

or

Imipenem/Cilastatin 1 g 8-hourly

or

As a carbapenem-sparing regimen

Piperacillin/Tazobactam 4.5 g 6-hourly + Tigecycline 100 mg initial dose, then 50 mg 12-hourly

+/-

In patients at high risk for invasive candidiasis

Fluconazole 800 mg LD then 400 mg 24-hourly

In patients with documented beta-lactam allergy consider use of antibiotic combinations with Amikacin 15–20 mg/kg 24-hourly

Empiric antimicrobial regimens for critically ill patients with healthcare-associated IAIs. Normal renal function

Healthcare-associated IAIs

Critically ill patients

Meropenem 1 g 8-hourly

or

Doripenem 500 mg 8-hourly

or

Imipenem/Cilastatin 1 g 8-hourly

or

As a carbapenem-sparing regimen

Ceftolozane /Tazobactam 1.5 g 8-hourly + Metronidazole 500 mg 6-hourly

or

Ceftazidime/Avibactam 2.5 g 8-hourly + Metronidazole 500 mg 6-hourly

 

+

Vancomycin 25–30 mg/kg loading dose then 15–20 mg/kg/dose 8-hourly

or

Teicoplanin 12 mg/kg 12-hourly times 3 loading dose then 12 mg/kg 24-hourly

or

In patients at risk for infection with vancomycin-resistant enterococci (VRE) including patients with previous enterococcal infection or colonization, immunocompromised patients, patients with long ICU stay, or recent Vancomycin exposure

Linezolid 600 mg 12-hourly

or

Daptomycin 6 mg/kg 24-hourly

+-

In patients at high risk for invasive candidiasis

Echinocandins: caspofungin (70 mg LD, then 50 mg daily), anidulafungin (200 mg LD, then 100 mg daily), micafungin (100 mg daily) or Amphotericin B Liposomal 3 mg/kg/dose 24-hourly.

In patients with suspected or proven infection with MDR (non-metallo-beta-lactamase-producing) Pseudomonas aeruginosa consider use of antibiotic combinations with Ceftolozane /Tazobactam.

In patients with suspected or proven infection with carbapenemase-producing Klebsiella pneumoniae consider use of antibiotic combinations with Ceftazidime/Avibactam.

In patients with documented beta-lactam allergy consider use of antibiotic combinations with Amikacin 15–20 mg/kg 24-hourly.

 

References

Sartelli M, Viale P, Catena F, Ansaloni L, Moore E, Malangoni M, et al. 2013 WSES guidelines for management of intra-abdominal infections. World J Emerg Surg. 2013;8:3.

Sartelli M, Weber DG, Ruppé E, Bassetti M, Wright BJ, Ansaloni L, et al. Antimicrobials: a global alliance for optimizing their rational use in intra-abdominal infections (AGORA). World J Emerg Surg. 2016;11:33.

Sartelli M, Chichom-Mefire A, Labricciosa FM, Hardcastle T, Abu-Zidan FM, Adesunkanmi AK, et al. The management of intra-abdominal infections from a global perspective: 2017 WSES guidelines for management of intra-abdominal infections. World J Emerg Surg. 2017 10;12:29.

Sartelli M, Catena F, Abu-Zidan FM, Ansaloni L, Biffl WL, Boermeester MA, et al. Management of intra-abdominal infections: recommendations by the WSES 2016 consensus conference. World J Emerg Surg. 2017 May 4;12:22.