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The management of carbapenem-resistant infections is often based on polymyxins, tigecycline, aminoglycosides and their combinations. However, in a recent systematic review, we found that Gram-negative bacteria (GNB) co-resistant to carbapanems, aminoglycosides, polymyxins and tigecycline (CAPT-resistant) are increasingly being reported worldwide. Clinical data to guide the treatment of CAPT-resistant GNB are scarce and based exclusively on few case reports and small case series, but seem to indicate that appropriate (in vitro active) antimicrobial regimens, including newer antibiotics and synergistic combinations, may be associated with lower mortality. In this review, we consolidate the available literature to inform clinicians dealing with CAPT-resistant GNB about treatment options by considering the mechanisms of resistance to carbapenems. In combination with rapid diagnostic methods that allow fast detection of carbapenemase production, the approach proposed in this review may guide a timely and targeted treatment of patients with infections by CAPT-resistant GNB. Specifically, we focus on the three most problematic species, namely Klebsiella pneumoniae, Pseudomonas aeruginosa and Acinetobacter baumannii. Several treatment options are currently available for CAPT-resistant K. pneumonia. Newer β-lactam-β-lactamase combinations, including the combination of ceftazidime/avibactam with aztreonam against metallo-β-lactamase-producing isolates, appear to be more effective compared to combinations of older agents. Options for P. aeruginosa (especially metallo-β-lactamase-producing strains) and A. baumannii remain limited. Synergistic combination of older agents (e.g., polymyxin- or fosfomycin-based synergistic combinations) may represent a last resort option, but their use against CAPT-resistant GNB requires further study.

Objectives: To identify the roles of various antibiotics as risk factors for carbapenem-resistant extended-spectrum β-lactamase (ESBL)-producing Klebsiella pneumoniae (KP) infection (ESBL-KP infection)., Methods: Data were collected over 26 months in a tertiary care university hospital with established endemicity of carbapenem-resistant ESBL-KP (ESBL-CRKP). Using a case-case-control design, patients who presented an infection caused by carbapenem-susceptible ESBL-KP (ESBL-CSKP) and patients with ESBL-CRKP infection were compared with a common control group of hospitalized patients. Effects of treatment and duration of treatment with antibiotics were examined, adjusting for major non-antibiotic risk factors and controlling for confounding effects among the antibiotics via logistic regression models., Results: Ninety-six ESBL-CRKP cases, 55 ESBL-CSKP cases and 151 controls were analysed. Multivariate analysis, adjusting for major non-antibiotic risk factors, showed that the risk of ESBL-CRKP infection rose with increasing duration of prior treatment with β-lactam/β-lactamase inhibitor combinations [odds ratio (OR) 1.15 per day increase; P = 0.001] and revealed that increased duration of treatment with fluoroquinolones amplified the impact of exposure to carbapenems (and vice versa) on ESBL-CRKP infection risk (OR 1.02 for interaction term; P = 0.009). Duration of prior treatment with fluoroquinolones was also associated with increased risk of ESBL-CSKP infection (OR 1.07 per day increase; P = 0.028), while prior receipt of carbapenems presented a protective effect against ESBL-CSKP infection (OR 0.21; P = 0.003)., Conclusions: This study highlights the major role of treatment and duration of treatment with β-lactam/β-lactamase inhibitor combinations and combinations of carbapenems with fluoroquinolones. Clinicians should counterweight the potential benefits of administering these antibiotics against the increased risk of ESBL-CRKP infection.

Background: The literature on the epidemiology, mortality and treatment of pandrug-resistant (PDR) Gram-negative bacteria (GNB) is scarce, scattered and controversial.Objectives: To consolidate the relevant literature and identify treatment options for PDR GNB infections.Methods: A systematic search in MEDLINE, Scopus and clinical trial registries was conducted. Studies reporting PDR clinical isolates were eligible for review if susceptibility testing for all major antimicrobials had been performed. Characteristics and findings of retrieved studies were qualitatively synthesized.Results: Of 81 studies reviewed, 47 (58%) were published in the last 5 years. The reports reflected a worldwide dissemination of PDR GNB in 25 countries in 5 continents. Of 526 PDR isolates reported, Pseudomonas aeruginosa (n=175), Acinetobacter baumannii (n=172) and Klebsiella pneumoniae (n=125) were most common. PDR GNB were typically isolated in ICUs, but several studies demonstrated wider outbreak potential, including dissemination to long-term care facilities and international spread. All-cause mortality was high (range 20%-71%), but appeared to be substantially reduced in studies reporting treatment regimens active in vitro. No controlled trial has been performed to date, but several case reports and series noted successful use of various regimens, predominantly synergistic combinations, and in selected patients increased exposure regimens and newer antibiotics.Conclusions: PDR GNB are increasingly being reported worldwide and are associated with high mortality. Several treatment regimens have been successfully used, of which synergistic combinations appear to be most promising and often the only available option. More pharmacokinetic/pharmacodynamic and outcome studies are needed to guide the use of synergistic combinations. [ABSTRACT FROM AUTHOR]

Objectives To identify the roles of various antibiotics as risk factors for carbapenem-resistant extended-spectrum β-lactamase (ESBL)-producing Klebsiella pneumoniae (KP) infection (ESBL-KP infection). Methods Data were collected over 26 months in a tertiary care university hospital with established endemicity of carbapenem-resistant ESBL-KP (ESBL-CRKP). Using a case–case–control design, patients who presented an infection caused by carbapenem-susceptible ESBL-KP (ESBL-CSKP) and patients with ESBL-CRKP infection were compared with a common control group of hospitalized patients. Effects of treatment and duration of treatment with antibiotics were examined, adjusting for major non-antibiotic risk factors and controlling for confounding effects among the antibiotics via logistic regression models. Results Ninety-six ESBL-CRKP cases, 55 ESBL-CSKP cases and 151 controls were analysed. Multivariate analysis, adjusting for major non-antibiotic risk factors, showed that the risk of ESBL-CRKP infection rose with increasing duration of prior treatment with β-lactam/β-lactamase inhibitor combinations [odds ratio (OR) 1.15 per day increase; P = 0.001] and revealed that increased duration of treatment with fluoroquinolones amplified the impact of exposure to carbapenems (and vice versa) on ESBL-CRKP infection risk (OR 1.02 for interaction term; P = 0.009). Duration of prior treatment with fluoroquinolones was also associated with increased risk of ESBL-CSKP infection (OR 1.07 per day increase; P = 0.028), while prior receipt of carbapenems presented a protective effect against ESBL-CSKP infection (OR 0.21; P = 0.003). Conclusions This study highlights the major role of treatment and duration of treatment with β-lactam/β-lactamase inhibitor combinations and combinations of carbapenems with fluoroquinolones. Clinicians should counterweight the potential benefits of administering these antibiotics against the increased risk of ESBL-CRKP infection. [ABSTRACT FROM PUBLISHER]