Antibiotics should be used after a treatable infection has been recognized or if there is a high degree of suspicion of an infection. The prolonged and inappropriate use of antibiotics appears a key factor in the rapid rise of antimicrobial resistance worldwide over the past decade. A rational and appropriate use of antibiotics is particularly important both to optimize quality clinical care and to reduce selection pressure on resistant pathogens. Several strategies aiming at achieving optimal use of antimicrobial agents have been described, but it is important that surgeons know antibiotic administration minimal requirements. Without these minimal requirements, surgeons worldwide will increase the likelihood of treatment failures and antibiotic resistance.
In the setting of uncomplicated intra-abdominal infections (IAIs) such as uncomplicated appendicitis or cholecystitis, single doses have the same impact as multiple doses and post-operative antimicrobial therapy is not necessary if source control is adequate.
In the setting of complicated IAIs, a short course of antibiotic therapy (3–5 days) after adequate source control is a reasonable option. The recent prospective trial by Sawyer et al. demonstrated that in patients with cIAI undergoing an adequate source control, the outcomes after approximately 4 days fixed-duration antibiotic therapy were similar to those after a longer course of antibiotics that extended until after the resolution of physiological abnormalities. However, in critically ill patients with ongoing sepsis, an individualized approach should be always mandatory and patient’s inflammatory response should be monitored regularly and decisions to continue, narrow, or stop antimicrobial therapy must be made on the basis of clinician and laboratory (such as procalcitonin) judgment.
Patients who have ongoing signs of peritonitis or systemic illness beyond 5–7 days of antibiotic treatment normally warrant a diagnostic investigation to determine whether additional surgical intervention is necessary to address an ongoing uncontrolled source of infection or antimicrobial treatment failure.
The choice of empiric antibiotic regimens in patients with IAI should be based on the local resistance epidemiology the individual risk for infection by resistant pathogens, and the clinical condition of the patients.
Knowledge of regional/local rates of resistance, when it is available, should be always an essential component of the clinical decision-making process when deciding the empirical treatment of infection. Regional epidemiological data and resistance profiles are essential for selecting appropriate antibiotic therapy for IAIs. However, while high-income countries (HICs) have extensive surveillance systems to monitor antimicrobial resistance, in low- and middle-income countries (LMICs) surveillance systems have not really been established. The Study for Monitoring Antimicrobial Resistance Trends (SMART) provides the best available evidence for the current status of cIAIs worldwide. The SMART has monitored the in vitro susceptibility patterns of clinical gram-negative bacilli to antimicrobial agents collected worldwide from intra-abdominal infections since 2002. Isolates worldwide showed the highest levels of antimicrobial resistance of the global regions included the SMART study, and a trend of increasing resistance continues year by year. One particular cause for concern is the prevalence of extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae in the clinical setting. The prevalence of ESBLs intra-abdominal infections has steadily increased over time for in Asia. Europe, Latin America, Middle East, North America, and South Pacific. In addition to the expected increased resistance to beta-lactams, fluoroquinolone resistance in ESBL-positive Escherichia coli causing intra-abdominal infections ranges from 60 to 93% in India, China, North America, Europe, and South Africa. Although carbapenem activity against isolates from IAIs is also high, it is slightly lower than activity against Klebsiella pneumoniae isolates from urinary tract infections.
Predicting the pathogens and potential resistance patterns of a given infection begins by establishing whether the infection is community-acquired or hospital-associated (nosocomial).
The major pathogens involved in community-acquired intra-abdominal infections are Enterobacteriaceae, Streptococcus species, and anaerobes (especially B. fragilis).
Contrastingly, the spectrum of microorganisms involved in nosocomial infections is significantly broader. In the past 20 years, the incidence of healthcare-associated infections caused by drug-resistant microorganisms has risen dramatically, probably in correlation with escalating levels of antibiotic exposure and increasing frequency of patients with one or more predisposing conditions, including elevated severity of illness, advanced age, degree of organ dysfunction, low albumin levels, poor nutritional status, immunodepression, presence of malignancy, and other comorbidities.
Although the transmission of multidrug-resistant organisms is most frequently observed in acute care facilities, all healthcare settings are affected by the emergence of drug-resistant pathogens.
In the context of intra-abdominal infections, the main resistance problem is posed by ESBL-producing Enterobacteriaceae, which are alarmingly prevalent in nosocomial infections and frequently observed in community-acquired infections, albeit to a lesser extent. Although a variety of factors can increase the risk of selection for ESBL producers, the most significant risk factors include prior exposure to antibiotics (especially third generation cephalosporins or fluoroquinolones) and comorbidities requiring concurrent antibiotic therapy.
For patients with sepsis or septic shock, early and properly administered empirical antimicrobial therapy can have a significant impact on the outcome, independent of the anatomical site of infection. International guidelines for the management of sepsis and septic shock (the Surviving Sepsis Campaign) recommend intravenously administered antibiotics within the first hour of onset of sepsis and septic shock and the use of broad-spectrum agents with adequate penetration of the presumed site of infection. Additionally, the employed antimicrobial regimen should be reassessed daily in order to optimize efficacy, prevent toxicity, minimize cost, and reduce selection pressures favoring resistant strains.
The antibiotic dosing regimen should be established depending on host factors and properties of antibiotic agents. Antibiotic pharmacokinetics describes the fundamental processes of absorption, distribution, metabolism, and elimination and the resulting concentration-versus-time profile of an agent administered in vivo. The achievement of appropriate target site concentrations of antibiotics is essential to eradicate the relevant pathogen. Suboptimal target site concentrations may have important clinical implications, and may explain therapeutic failures, in particular, for bacteria for which in vitro MICs are high. Antibiotics typically need to reach a site of action outside the plasma. This requires the drug to pass through the capillary membranes. Disease and drug-related factors can contribute to differential tissue distribution.
In patients with septic shock, administering an optimal first dose is probably as equally important as to the timing of administration. This optimal first dose could be described as a loading, or front-loaded dose and is calculated from the volume of distribution (Vd) of the drug and the desired plasma concentration. The Vd of hydrophilic agents (which disperse mainly in water such as beta-lactams) in patients with septic shock may be altered by changes in the permeability of the microvascular endothelium and consequent alterations in extracellular body water. This may lead to lower than expected plasma concentrations during the first day of therapy resulting in sub-optimal achievement of antibiotic levels. In the setting of alterations in the volume of distribution, loading doses and/or a higher overall total daily dose of beta-lactams are often required to maximize the pharmodynamics ensuring optimal drug exposure to the infection site in patients with sepsis or septic shock.
Once an appropriate initial loading dose is achieved, the antibiotic regimen should be reassessed, at least daily, because pathophysiological changes may significantly affect drug availability in the critically ill patients. Lower than standard dosages of renally excreted drugs must be administered in the presence of impaired renal function, while higher than standard dosages of renally excreted drugs may be needed for optimal activity in patients with glomerular hyperfiltration. It should be noted that in critically ill patients, plasma creatinine is an unreliable marker of renal function.
Recommended dosing regimens of the most frequently used renally excreted antimicrobials according to renal function
Knowledge of the pharmacokinetic and pharmacodynamic antibiotic properties of each drug including (inhibition of growth, rate and extent of bactericidal action, and post-antibiotic effect) may provide a more rational determination of optimal dosing regimens in terms of the dose and the dosing interval. Optimal use of the pharmacokinetic/pharmacodynamic relationship of antibiotics is important for obtaining good clinical outcomes and reduction of resistance. Dosing frequency is related to the concept of time-dependent versus concentration-dependent killing. Beta-lactams exhibit time-dependent activity and exert optimal bactericidal activity when drug concentrations are maintained above the MIC. Therefore, it is important that the serum concentration exceeds the MIC for appropriate duration of the dosing interval for the antimicrobial and the organism. Higher frequency dosing, prolonged infusions and continuous infusions have been utilized to achieve this effect. Basing on pharmacokinetics/pharmacodynamics principles the traditional intermittent dosing of each agent may be replaced with prolonged infusions of certain beta-lactam antibiotics especially in those critically ill patients with infections caused by Gram-negative bacilli that have elevated but susceptible MICs to the chosen agent.
In contrast, antibiotics such as aminoglycosides exhibit concentration-dependent activity and should be administered in a once daily manner (or with the least possible number of daily administrations) in order to achieve high peak plasma concentrations. With these agents, the peak serum concentration, and not the time the concentration remains above the MIC, is more closely associated with efficacy. In terms of toxicity, aminoglycosides nephrotoxicity is caused by a direct effect on the renal cortex and its uptake saturation. Thus, an extended interval dosing strategy reduces the renal cortex exposure to aminoglycosides and reduces the risk of nephrotoxicity.
Intra-abdominal infections may be managed with either single or multiple antibiotic regimens.
Beta-lactam/beta-lactamase inhibitor combinations have an in vitro activity against gram-positive, gram-negative, and anaerobe organisms. Amoxicillin/clavulanate is still an option in mild community acquired IAIs. Broad-spectrum activity of piperacillin/tazobactam, including anti-Pseudomonas effect and anaerobic coverage, still make it an interesting option for management of severe IAIs. The efficacy of piperacillin-tazobactam for treating serious ESBL infections is controversial. Yet, there have been concerns that in vitro susceptibility may not reliably translate into clinical efficacy. This has been based largely on concerns over inoculum effects, the co-location of other beta-lactamase enzymes (which may not be well inhibited by beta-lactamase inhibitors) on acquired plasmids and the potential for additional resistance mechanisms such as alterations in outer membrane proteins. Furthermore, in critically ill patients the pharmacokinetic properties of beta-lactam agents are modified and these patients may have adverse outcomes as a result of sub-optimal antibiotic exposure.
Third generation cephalosporins including cefotaxime and ceftriaxone in association with metronidazole, may be still options for the treatment of mild IAIs. Ceftazidime and cefoperazone are third generation cephalosporins with an activity against P. aeruginosa. Cefepime, a fourth-generation cephalosporin with broader spectrum activity compared to ceftriaxone, is a poor inducer of AmpC beta-lactamase. Many AmpC-producing organisms are susceptible to cefepime because cefepime is poorly hydrolyzed by the AmpC beta-lactamase enzyme. However, the role of cefepime in treating infections caused by AmpC-producing organisms is controversial because of the inoculum effect.
Ciprofloxacin and levofloxacin are no longer appropriate choice as first-line treatment in many geographic regions because of the prevalence of fluoroquinolone resistance. However, when employed, these drugs should be used in association with metronidazole. In many current practices, the fluoroquinolones remain available for patients presenting allergy to beta-lactams, with mild intra-abdominal infections.
Carbapenems offer a wide spectrum of antimicrobial activity against gram-positive and gram-negative aerobic and anaerobic pathogens (with the exception of MDR-resistant gram-positive cocci). Group 1 carbapenems include ertapenem. This group has activity against extended-spectrum beta-lactamase (ESBL)-producing pathogens, but not active against P. aeruginosa and Enterococcus species. Group 2 includes imipenem/cilastatin, meropenem, and doripenem, which share activity against non-fermentative gram-negative bacilli.
For more than two decades, carbapenems have been considered the agents of choice for multidrug-resistant infections caused by Enterobacteriaceae. The recent and rapid spread K. pneumoniae carbapenems resistant has become a critical issue in hospitals worldwide. The use of carbapenems should be limited so as to preserve activity of this class of antibiotics because of the concern of emerging carbapenem-resistance.
Other options include aminoglycosides, particularly for suspected infections by gram-negative bacteria. They are effective against P. aeruginosa, but are ineffective against anaerobic bacteria and need association with metronidazole. Because of their toxic side effects, some guidelines did not recommend aminoglycosides for the routine empiric treatment of community-acquired IAI, reserving them for patients with allergies to beta-lactam agents or in combination with beta-lactams for treatment of IAI with suspected MDR gram-negative bacteria.
Tigecycline is a viable treatment option, especially in empiric therapy, for complicated IAIs due to its favorable in vitro activity against anaerobic organisms, enterococci, several ESBL- and in association carbapenemase-producing Enterobacteriaceae, Acinetobacter species, and Stenotrophomonas maltophilia. It does not feature in vitro activity against P. aeruginosa or P. mirabilis. Caution is always advised for its use, in suspected bacteremia and hospital-acquired pneumonia.
The recent challenges of treating multidrug-resistant gram-negative infections, especially in critically ill patients, have renewed interest in the use of “old” antibiotics such as polymyxins and fosfomycin, now routinely used for treatment of MDR bacteria in critical ill patients.
Ceftolozone/tazobactam and ceftazidime/avibactam are new antibiotics that have been approved for treatment of cIAIs (in combination with metronidazole) including infection by ESBLs producing Enterobacteriaceae and P. aeruginosa. These antimicrobials will be valuable for treating infections caused by MDR gram-negative bacteria in order to preserve carbapenems. Ceftolozone/tazobactam has excellent in vitro activity against MDR Psudomonas. aeruginosa. Ceftazidime/avibactam has an in vitro activity against K. pneumoniae carbapenemase-producing bacteria. Although many reviews have been written, their precise role as empiric treatment for complicated IAI remains to be defined.
Hawser SP, Bouchillon SK, Hoban DJ, Badal RE. In vitro susceptibilities of aerobic and facultative anaerobic gram-negative bacilli from patients with intra-abdominal infections worldwide from 2005–2007: results from the SMART study. Int J Antimicrob Agents. 2009;34:585–8.
Morrissey I, Hackel M, Badal R, Bouchillon S, Hawser S, Biedenbach D. A review of ten years of the Study for Monitoring Antimicrobial Resistance Trends (SMART) from 2002 to 2011. Pharmaceuticals (Basel). 2013;6:1335–46.
Sawyer RG, Claridge JA, Nathens AB, Rotstein OD, Duane TM, Evans HL, et al. Trial of short-course antimicrobial therapy for intraabdominal infection. N Engl J Med. 2015;372:1996–2005.
Mazuski JE. Antimicrobial treatment for intra-abdominal infections. Expert Opin Pharmacother. 2007;8:2933–45.
Kaye KS, Pogue JM. Infections caused by resistant gram-negative bacteria: epidemiology and management. Pharmacotherapy. 2015;35:949–62.
Ruppé E, Armand-Lefèvre L, Estellat C, Consigny PH, El Mniai A, Boussadia Y, et al. High rate of acquisition but short duration of carriage of multidrug-resistant Enterobacteriaceae after travel to the tropics. Clin Infect Dis. 2015;61:593–600.
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.