Choice of therapeutic interventions and outcomes for the treatment of infections caused by multidrug-resistant gram-negative pathogens: a systematic review

Background Antimicrobial resistance is an increasingly serious threat to public health, and the increased occurrence of multidrug-resistant (MDR) bacteria is a concern in both high-income and low- and middle-income countries. The purpose of this systematic review was to identify and critically appraise current antimicrobial treatment options for infections with MDR Gram-negative bacteria. Methods A literature search for treatment of MDR extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae, A. baumannii, and P. aeruginosa was conducted in MEDLINE in January 2019. Relevant studies published in English, German, and French that evaluated clinical success, microbiological success, and 30-day mortality outcomes were included. The population of interest was adult patients. Results Of 672 studies, 43 met the inclusion criteria. Carbapenems are the most common antibiotics used for the treatment of ESBL-producing Enterobacteriaceae. The clinical and microbiological success was similar for group 1 carbapenems (imipenem, meropenem, or doripenem), group 2 carbapenems (ertapenem), and non-carbapenem antibiotics. Mortality data were contradictory for group 1 carbapenems compared to group 2 carbapenems. The most common treatment option for A. baumannii and P. aeruginosa infections was intravenous colistin, regardless of infection site. Clinical success and mortality were similar in A. baumannii infections treated with colistin combination therapy vs. colistin monotherapy, whereas heterogeneous results were found with respect to microbiological success. Monotherapy and colistin combination therapy were used against P. aeruginosa with clinical and microbiological success (70-100%) depending on the infection site and severity, and the antibiotic used. Ceftazidime-avibactam therapy for ESBL-producing Enterobacteriaceae and P. aeruginosa showed good clinical success in one study. Conclusion We did not find robust evidence for antibiotic treatment of any infection with MDR Gram-negative bacteria, including ESBL-producing Enterobacteriaceae, A. baumannii, and P. aeruginosa, that would lead to a firm recommendation for one specific antibiotic over another or for monotherapy over combination therapy. The choice of antibiotic treatment should be based on susceptibility testing balancing the expected clinical success rate against the risk of development of antibiotic resistance and the risk of severe side effects.