Editorial for the special issue: “Epidemiology, prognosis and antimicrobial treatment of extensively antibiotic-resistant bacterial infections”

The increasing consumption of broad-spectrum antimicrobials is fuelling a vicious cycle leading to extensively drug-resistant (XDR) and pandrug-resistant (PDR) bacteria [...

Pandrug-resistant Gram-negative bacteria : a systematic review of current epidemiology, prognosis and treatment options

Background: The literature on the epidemiology, mortality and treatment of pandrug-resistant (PDR) Gram-negative bacteria (GNB) is scarce, scattered and controversial. Objective: 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 intensive care units, 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. Conclusion: 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

Cefiderocol: systematic review of mechanisms of resistance, heteroresistance and in vivo emergence of resistance

Cefiderocol appears promising, as it can overcome most β-lactam resistance mechanisms (including β-lactamases, porin mutations, and efflux pumps). Resistance is uncommon according to large multinational cohorts, including against isolates resistant to carbapenems, ceftazidime/avibactam, ceftolozane/tazobactam, and colistin. However, alarming proportions of resistance have been reported in some recent cohorts (up to 50%). A systematic review was conducted in PubMed and Scopus from inception to May 2022 to review mechanisms of resistance, prevalence of heteroresistance, and in vivo emergence of resistance to cefiderocol during treatment. A variety of mechanisms, typically acting in concert, have been reported to confer resistance to cefiderocol: β-lactamases (especially NDM, KPC and AmpC variants conferring resistance to ceftazidime/avibactam, OXA-427, and PER- and SHV-type ESBLs), porin mutations, and mutations affecting siderophore receptors, efflux pumps, and target (PBP-3) modifications. Coexpression of multiple β-lactamases, often in combination with permeability defects, appears to be the main mechanism of resistance. Heteroresistance is highly prevalent (especially in A. baumannii), but its clinical impact is unclear, considering that in vivo emergence of resistance appears to be low in clinical studies. Nevertheless, cases of in vivo emerging cefiderocol resistance are increasingly being reported. Continued surveillance of cefiderocol’s activity is important as this agent is introduced in clinical practice

Global prevalence of cefiderocol non-susceptibility in Enterobacterales, Pseudomonas aeruginosa, Acinetobacter baumannii and Stenotrophomonas maltophilia: a systematic review and meta-analysis

Background Cefiderocol is a last resort option for carbapenem-resistant (CR) Gram-negative bacteria, especially metallo-β-lactamase (MBL)-producing Pseudomonas aeruginosa and CR Acinetobacter baumannii. Monitoring global levels of cefiderocol non-susceptibility (CFDC-NS) is important. Objectives To systematically collate and examine studies investigating in-vitro CFDC-NS and estimate the global prevalence of CFDC-NS against major Gram-negative pathogens. Data sources PubMed and Scopus, up to May 2023. Study eligibility criteria Eligible were studies reporting CFDC-NS in Enterobacterales, P. aeruginosa, A. baumannii, or Stenotrophomonas maltophilia clinical isolates. Methods Two independent reviewers extracted study data and assessed risk of bias on the population, setting and measurement (susceptibility testing) domains. Binomial-Normal mixed-effects models were applied to estimate CFDC-NS prevalence by species, co-resistance phenotype and breakpoint definition (EUCAST, CLSI, FDA). Sources of heterogeneity were investigated by subgroup and meta-regression analyses. Results In all, 78 studies reporting 82,035 clinical isolates were analysed (87% published between 2020 and 2023). CFDC-NS prevalence (EUCAST breakpoints) was low overall, but varied by species [S. maltophilia 0.4% (95%CI 0.2-0.7%), Enterobacterales 3.0% (95%CI 1.5-6.0%), P. aeruginosa 1.4% (95%CI 0.5-4.0%)] and was highest for A. baumannii (8.8%, 95%CI 4.9-15.2%). CFDC-NS was much higher in CR Enterobacterales (12.4%, 95%CI 7.3-20.0%) and CR A. baumannii (13.2%, 95%CI 7.8-21.5%), but relatively low for CR P. aeruginosa (3.5%, 95%CI 1.6-7.8%). CFDC-NS was exceedingly high in NDM-producing Enterobacterales (38.8%, 95%CI 22.6-58.0%), NDM-producing A. baumannii (44.7%, 95%CI 34.5-55.4%), and ceftazidime/avibactam-resistant Enterobacterales (36.6%, 95%CI 22.7-53.1%). CFDC-NS varied considerably with breakpoint definition, predominantly among CR bacteria. Additional sources of heterogeneity were single-centre investigations and geographical regions. Conclusions CFDC-NS prevalence is low overall, but alarmingly high for specific CR phenotypes circulating in some institutions or regions. Continuous surveillance and updating of global CFDC-NS estimates are imperative while cefiderocol is increasingly introduced into clinical practice. The need to harmonize EUCAST and CLSI breakpoints was evident

Domino-style earthquakes along blind normal faults in Northern Thessaly (Greece): kinematic evidence from field observations, seismology, SAR interferometry and GNSS

Here we present a joint analysis of the geodetic, seismological and geological data of the March 2021 Northern Thessaly seismic sequence, that were gathered and processed as of April 30, 2021. First, we relocated seismicity data from regional and local networks and inferred the dip-direction (NE) and dip-angle (38°) of the March 3, 2021 rupture plane. Furthermore, we used ascending and descending SAR images acquired by the Sentinel-1 satellites to map the co-seismic displacement field. Our results indicate that the March 3, 2021 Mw=6.3 rupture occurred on a NE-dipping, 39° normal fault located between the villages Zarko (Trikala) and Damasi (Larissa). The event of March 4, 2021 occurred northwest of Damasi, along a fault oriented WNW-ESE and produced less deformation than the event of the previous day. The third event occurred on March 12, 2021 along a south-dipping normal fault. We computed 22 focal mechanisms of aftershocks with M≥4.0 using P-wave first motion polarities. Nearly all focal mechanisms exhibit normal kinematics or have a dominant normal dip-slip component. The use of InSAR was crucial to differentiate the ground deformation between the ruptures. The majority of deformation occurs in the vertical component, with a maximum of 0.39 m of subsidence over the Mw=6.3 rupture plane, south and west of Damasi. A total amount of 0.3 m horizontal displacement (E-W) was measured. We also used GNSS data (at 30-s sampling interval) from twelve permanent stations near the epicentres to obtain 3D seismic offsets of station positions. Only the first event produces significant displacement at the GNSS stations (as predicted by the fault models, themselves very well constrained by InSAR). We calculated several post-seismic interferograms, yet we have observed that there is almost no post-seismic deformation, except in the footwall area (Zarkos mountain). This post-seismic deformation is below the 7 mm level (quarter of a fringe) in the near field and below the 1 mm level at the GNSS sites. The cascading activation of the three events in a SE to NW direction points to a pattern of domino-style earthquakes, along neighbouring fault segments. The kinematics of the ruptures point to a counter-clockwise change in the extension direction of the upper crust (from NE-SW near Damasi to N-S towards northwest, near Verdikoussa)

Systematic review and meta-analysis of the proportion and associated mortality of polymicrobial (vs monomicrobial) pulmonary and bloodstream infections by Acinetobacter baumannii complex

Background Differentiating Acinetobacter baumannii complex (ABC) infection from colonization remains difficult and further complicated in polymicrobial infections. Purpose To assess the frequency of polymicrobial ABC infections and associated mortality. We hypothesized a lower mortality in polymicrobial infections if ABC isolation reflects colonization in some polymicrobial infections. Methods A systematic review was conducted in PubMed, Scopus and CENTRAL for studies reporting ABC pulmonary and bloodstream infections. The proportion of infections that were polymicrobial and the magnitude of the association between polymicrobial (vs monomicrobial) infection and mortality were estimated with meta-analyses. Results Based on 80 studies (9759 infections) from 23 countries, the pooled proportion of polymicrobial infection was 27% (95% CI 22–31%) and was similarly high for bloodstream and pulmonary infections. Polymicrobial infection was variably and insufficiently defined in most (95%) studies. Considerable heterogeneity (I2 = 95%) was observed that persisted in subgroup analyses and meta-regressions. Based on 17 studies (2675 infections), polymicrobial infection was associated with lower 28-day mortality (OR = 0.75, 95% CI 0.58–0.98, I2 = 36%). However, polymicrobial infection was not associated with in-hospital mortality (OR = 0.97, 95% CI 0.69–1.35, I2 = 0%) based on 14 studies (953 infections). The quality of evidence (GRADE) for the association of polymicrobial (vs monomicrobial) infection with mortality was low and at high risk of bias. Conclusion Polymicrobial ABC infections are common and may be associated with lower 28-day mortality. Considering the heterogeneity of polymicrobial infections and limitations of the available literature, more research is required to clarify the clinical impact of polymicrobial (vs monomicrobial) ABC infection