Get shorty!

A recent randomized controlled trial to evaluate the efficacy of a fixed, short antimicrobial treatment was published in May of this year (1). This interesting study brings to the fore the importance of evaluating, with proper methodology, one of the most disputable aspects of antimicrobial treatments, the duration. When supported by strong evidence or expert statements, shortening courses of antimicrobial treatments are an important component of antimicrobial stewardship programs (2). The course of therapy must be defined as the time period during which therapeutic concentrations are maintained at the site of infection, instead of the time during which an antimicrobial treatment is administered. This definition puts emphasis on the importance of a thorough evaluation before starting a short treatment. For example, the most recent Infectious Diseases Society of America (IDSA) skin and soft tissue guidelines suggest a treatment as short as five days for cellulitis (3). This duration might not apply to a patient with cellulitis and chronic arterial insufficiency of the lower limbs. Successful abbreviated treatment courses depend on several factors linked to host (immune status), pathogen (susceptibility, low spontaneous mutation rate, extracellular, rapid multiplication), infection site (accessible site, not as biofilm, no foreign body, not lifethreatening, not in an abscess – low pH, or any other factors that inhibit antimicrobial action) and therapeutic agents (bactericidal, rapid onset of action, lack of propensity to induce mutants, good penetration in tissues, active against nondividing bacteria). This strategy has several theoretical or demonstrated advantages. There is a clear link between bacterial resistance and shorter courses of antimicrobial treatments. It reduces the selective pressure on bacterial flora and, therefore, prevents emergence of resistance. Upper respiratory tract infections treated for ≥5 days in children increased the risk of pharyngeal carriage of resistant Streptococcus pneumoniae (4). Prophylaxis for >48 h after cardiovascular surgery was associated with increased bacterial resistance in enterobacteriaceae and enterococci (5). However, one must remember that a useless short course is still the worst strategy and strength should also be put on avoiding the treatment of conditions that do not require antimicrobial treatments such as asymptomatic bacteriuria, upper respiratory viral infections and viral otitis media, etc. Other advantages of short therapy are increased compliance, reduced direct (related to the acquisition of an antimicrobial treatment) and indirect (associated with administration of intravenous antimicrobial treatments, adverse effects, length of stay, etc) costs, lower risk of adverse events and drug-drug interactions. The main drawback of a shorter treatment is the risk of lower efficacy that may be associated with additional treatment (probably with a broader spectrum because the patient failed the previous treatment), significant morbidity and hospital admissions/readmissions. There is a lower limit under which short therapy becomes ineffective and that is why we need sound studies to support it. Several studies have demonstrated the limit in shortening treatments because they were associated with unfavourable outcomes. Single-dose treatments for uncomplicated cystitis have been consistently shown to be less successful than longer courses (6) and treating Staphylococcus aureus bacteremia for <14 days was associated with higher relapse rates (7). In the 2010, Diagnosis and Management of Complicated Intraabdominal Infection in Adults and Children: Guidelines by the Surgical Infection Society and the Infectious Diseases Society of America, the recommended duration of an established infection was four to seven days in patients with adequate source control (8). At this time, it was graded as a B-III (moderate evidence coming mainly from expert opinion and descriptive studies). For some indications, suggested treatment or prophylaxis was even shorter. For stomach or proximal jejunum perforations, when source control was achieved, prophylactic antibiotics directed against aerobic Gram-positive cocci for 24 h were considered to be adequate, unless patients were undergoing treatment to reduce gastric acidity or were known for gastric malignancy. In these cases, antimicrobial therapy covering a mixed flora was recommended for the same duration. Penetrating bowel injuries repaired within 12 h, any intraoperative contamination by enteric contents, acute appendicitis without perforation, and abscess or local peritonitis should be treated with an antimicrobial treatment with mixed flora coverage for <24 h. The recent multicentre randomized controlled trial published by Sawyer et al (1) presents evidence to support a four-day treatment for complicated intra-abdominal infections, instead of the four to seven days suggested in the aforementioned guidelines. A total of 518 patients were enrolled and underwent randomization; 260 were assigned to a control group that received antimicrobial treatments until two days after the resolution of their sepsis (based on systemic inflammatory response syndrome criteria) and 258 received a fixed four-day course of therapy. To be included in the study, patients needed to have undergone an intervention to achieve source control. The choice of the antimicrobial agent was not dictated by the protocol but was considered acceptable if consistent with IDSA guidelines. The most frequently used antimicrobial treatment was piperacillin-tazobactam in 54% of patients. Baseline characteristics in the two groups were very similar. In the control group, patients received antimicrobial treatments for a median duration of eight days (interquartile range five to 10 days) versus four days (interquartile range four to five days) in the experimental group. The main outcomes of this study, surgical site infection and recurrent intraabdominal infection or death, were almost identical in both groups; 21.8% in the experimental group versus 22.3% in the control group (absolute difference −0.5 percentage point [95 % CI −7.0 to 8.0] [P=0.92]). The study had several strengths including a large sample size and randomized design, but above all, it included patients with Adult infectious diseAses notes