In vitro, in vivo and clinical studies comparing the efficacy of ceftazidime-avibactam monotherapy with ceftazidime-avibactam-containing combination regimens against carbapenem-resistant Enterobacterales and multidrug-resistant Pseudomonas aeruginosa isolates or infections: a scoping review

IntroductionCarbapenem-resistant Enterobacterales (CRE) and multidrug-resistant Pseudomonas aeruginosa (MDR-PA) infections are associated with a high risk of morbidity, mortality, and treatment costs. We aimed to evaluate in vitro, in vivo and clinical studies comparing the efficacy of ceftazidime-avibactam (CZA) combination regimens with CZA alone against CRE and/or MDR-PA isolates or infections.MethodsWe systematically reviewed the relevant literature in CINAHL/MEDLINE, Pubmed, Cochrane, Web of Science, Embase, and Scopus until December 1, 2022. Review articles, grey literature, abstracts, comments, editorials, non-peer reviewed articles, non-English articles, and in vitro synergy studies conducted on single isolates were excluded.Results22 in vitro, 7 in vivo and 20 clinical studies were evaluated. In vitro studies showed reliable synergy between CZA and aztreonam against metallo-β-lactamase (MBL)-producing isolates. Some studies indicated good in vitro synergy between CZA and amikacin, meropenem, fosfomycin and polymyxins against CRE isolates. For MDR-PA isolates, there are comparatively fewer in vitro or in vivo studies. In observational clinical studies, mortality, clinical cure, adverse events, and development of CZA resistance after exposure were generally similar in monotherapy and combination therapy groups. However, antibiotic-related nephrotoxicity and infection relapses were higher in patients receiving CZA combination therapies.DiscussionThe benefit, if any, of CZA combination regimens in MDR-PA infections is elusive, as very few clinical studies have included these infections. There is no currently documented clinical benefit for the use of CZA combination regimens rather than CZA monotherapy. CZA combined with aztreonam for serious infections due to MBL producers should be evaluated by randomized controlled trials.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/display_record.php?RecordID=278552, CRD42021278552

Impact of changes in the WHO's 2019 update of DDDs on the measurement of adult hospital antibacterial consumption in Catalonia (Spain), 2008-18

In 2019 the WHO fully adopted new DDD values. The objective of this study is to analyse their impact on the measurement of consumption of antibacterials in hospitals participating in the Catalan Infection Control and Antimicrobial Stewardship National Program (VINCat-PROA) in Catalonia (Spain) between 2008 and 2018. The anatomical therapeutic chemical/DDD system was used to monitor adult hospital antibacterial consumption expressed in DDD/100 bed-days. Consumption from 2008 to 2018 was calculated using both pre- and post-update DDD values. Differences were calculated as the percentage variation in DDD/100 bed-days and analysed with Student's t -test. Simple linear regressions were performed to evaluate the trends in adult antimicrobial consumption over the study period. The overall consumption according to post-update DDD values decreased by 12.2% (P < 0.001) compared with the pre-update DDD values. Penicillins (−19.6.%; P < 0.001) and carbapenems (−19.0%; P = 0.023) showed the greatest reduction, followed by cephalosporins (−7.7%; P = 0.021) and quinolone antibacterials (−7.7%; P = 0.017). ICU services showed the greatest overall reduction (−13.1%; P < 0.001). From 2008 to 2018 there was a statistically significant decrease in consumption of penicillins and quinolone antibacterials and a statistically significant increase in cephalosporin and carbapenem consumption with both pre- and post-update DDD values. There were no variations in the ranking of consumption between the pre- and post-update DDD values. The WHO's updates of DDDs have had a significant impact on the measurement of antibacterial consumption. In our region, they have corrected an overestimation of penicillin and carbapenem consumption amounting to 19%. It is essential to bear these findings in mind for an accurate assessment of temporal trends and benchmarking

Antimicrobial consumption among 66 acute care hospitals in Catalonia: impact of the COVID-19 pandemic

Background: antimicrobials have been widely used during the COVID-19 pandemic. This study aimed to analyze the impact of the COVID-19 pandemic on the antimicrobial consumption of 66 hospitals in Catalonia. Methods: adult antibacterial and antimycotic consumption was calculated as defined daily doses (DDD)/100 bed-days and DDD/100 discharges. Firstly, overall and ICU consumption in 2019 and 2020 were compared. Secondly, observed ICU 2020 consumptions were compared with non-COVID-19 2020 estimated consumptions (based on the trend from 2008-2019). Results: overall, antibacterial consumption increased by 2.31% and 4.15% DDD/100 bed-days and DDD/100 discharges, respectively. Azithromycin (105.4% and 109.08% DDD/100 bed-days and DDD/100 discharges, respectively) and ceftriaxone (25.72% and 27.97% DDD/100 bed-days and DDD/100 discharges, respectively) mainly accounted for this finding. Likewise, antifungal consumption increased by 10.25% DDD/100 bed-days and 12.22% DDD/100 discharges, mainly due to echinocandins or amphotericin B. ICU antibacterial and antimycotic consumption decreased by 1.28% and 4.35% DDD/100 bed-days, respectively. On the contrary, antibacterial and antifungal use, expressed in DDD/100 discharges, increased by 23.42% and 19.58%. Azithromycin (275.09%), ceftriaxone (55.11%), cefepime (106.35%), vancomycin (29.81%), linezolid (31.28%), amphotericin B (87.98%), and voriconazole (96.17%) use changed the most. Observed consumption of amphotericin B, azithromycin, caspofungin, ceftriaxone, vancomycin, and voriconazole were higher than estimated values. Conclusions: the consumption indicators for most antimicrobials deviated from the expected trend pattern. A worrisome increase in antibacterial and antifungal consumption was observed in ICUs in Catalonia

Impact of changes in the WHO's 2019 update of DDDs on the measurement of adult hospital antibacterial consumption in Catalonia, 2008-18

Objectives: in 2019 the WHO fully adopted new DDD values. The objective of this study is to analyse their impact on the measurement of consumption of antibacterials in hospitals participating in the Catalan Infection Control and Antimicrobial Stewardship National Program (VINCat-PROA) in Catalonia (Spain) between 2008 and 2018. Methods: the anatomical therapeutic chemical/DDD system was used to monitor adult hospital antibacterial consumption expressed in DDD/100 bed-days. Consumption from 2008 to 2018 was calculated using both pre- and post-update DDD values. Differences were calculated as the percentage variation in DDD/100 bed-days and analysed with Student's t-test. Simple linear regressions were performed to evaluate the trends in adult antimicrobial consumption over the study period. Results: the overall consumption according to post-update DDD values decreased by 12.2% (P < 0.001) compared with the pre-update DDD values. Penicillins (−19.6.%; P < 0.001) and carbapenems (−19.0%; P = 0.023) showed the greatest reduction, followed by cephalosporins (−7.7%; P = 0.021) and quinolone antibacterials (−7.7%; P = 0.017). ICU services showed the greatest overall reduction (−13.1%; P < 0.001). From 2008 to 2018 there was a statistically significant decrease in consumption of penicillins and quinolone antibacterials and a statistically significant increase in cephalosporin and carbapenem consumption with both pre- and post-update DDD values. There were no variations in the ranking of consumption between the pre- and post-update DDD values. Conclusions: the WHO's updates of DDDs have had a significant impact on the measurement of antibacterial consumption. In our region, they have corrected an overestimation of penicillin and carbapenem consumption amounting to 19%. It is essential to bear these findings in mind for an accurate assessment of temporal trends and benchmarking

A descriptive analysis of urinary ESBL-Producing-Escherichia coli in Cerdanya Hospital

Urinary tract infections caused by extended-spectrum β-lactamase Escherichia coli (ESBLEC) are increasing worldwide and are a current concern because treatment options are often limited. This study investigated antimicrobial susceptibility, antimicrobial resistance genes (ARGs), and the biological diversity of urinary ESBL-EC isolates at Cerdanya Hospital, a European cross-border hospital that combines French and Spanish healthcare models. Bacterial identification and susceptibility were determined using the Microscan WalkAway® system and ESBL production was examined by the double-disk synergy method. Isolates were sequenced using the Ion S5¿ next-generation sequencing system, with the whole-genome sequences then assembled using SPADEs software and analyzed using PubMLST, ResFinder, FimTyper, PlasmidFinder, and VirulenceFinder. A phylogenetic analysis was performed by constructing an assembly-based core-SNV alignment, followed by a phylogenetic tree constructed using Parsnp from the Harvest suite. All isolates studied were multidrug-resistant and could be classified into 19 different sequence types characterized by a high genetic diversity. The most prevalent ESBL-enzymes were CTX-M-14 and CTX-M-15. High-risk international clones (ST131, ST10, and ST405) were also identified. The results demonstrated the absence of a single predominant clone of ESBL-MDR-EC at Cerdanya Hospital

Pathogenesis of Staphylococcus epidermidis in prosthetic joint infections : can identification of virulence genes differentiate between infecting and commensal strains?

Background: Staphylococcus epidermidis is a commensal of human skin flora and a frequent causative micro-organism in prosthetic joint infections (PJIs). To date, no single marker has been identified to distinguish infecting strains from commensal S. epidermidis populations. Aim: To find possible genetic markers to distinguish between the two populations. Methods: Fifty S. epidermidis strains from patients with PJIs were analysed, 50 from the skin of healthy individuals (commensal strains) and 17 from the surgical field of patients undergoing primary arthroplasty. In these three groups the antimicrobial susceptibility profile, sequence type, biofilm formation, and virulence factors were studied. Strains from the surgical field have not been compared previously with strains from the other two groups. Findings: S. epidermidis strains from PJI patients were significantly more antibiotic resistant than commensal strains and surgical field strains. A wide variety of sequence types was found in commensal and surgical field strains. The predominant sequence type was ST2 and it was only present in PJI strains (44%). Differences in biofilm production did not differ between populations. Virulence genes sdrF and bhp, the complete ica operon, and the insertion sequence IS256 were significantly predominant in PJI strains. By contrast, embp and hld genes and the arginine catabolic mobile element (ACME) were more prevalent in commensal strains. Surgical field strains could be a valid control group to discriminate between infecting and commensal strains. Conclusion: A combination of characteristic features can differentiate between infecting and commensal S. epidermidis strains in PJI, whereas a single marker cannot

Virulence genes and subclone status as markers of experimental virulence in a murine sepsis model among Escherichia coli sequence type 131 clinical isolates from Spain

Objective: To assess experimental virulence among sequence type 131 (ST131) Escherichia coli bloodstream isolates in relation to virulence genotype and subclone. Methods: We analysed 48 Spanish ST131 bloodstream isolates (2010) by PCR for ST131 subclone status (H30Rx, H30 non-Rx, or non-H30), virulence genes (VGs), and O-type. Then we compared these traits with virulence in a murine sepsis model, as measured by illness severity score (ISS) and rapid lethality (mean ISS >= 4). Results: Of the 48 study isolates, 65% were H30Rx, 21% H30 non-Rx, and 15% non-H30; 44% produced ESBLs, 98% were O25b, and 83% qualified as extraintestinal pathogenic E. coli (ExPEC). Of 49 VGs, ibeA and iss were associated significantly with non-H30 isolates, and sat, iha and malX with H30 isolates. Median VG scores differed by subclone, i.e., 12 (H30Rx), 10 (H30 non-Rx), and 11 (non-H30) (p < 0.01). Nearly 80% of isolates represented a described virotype. In mice, H30Rx and non-H30 isolates were more virulent than H30 non-Rx isolates (according to ISS [p = 0.03] and rapid lethality [p = 0.03]), as were ExPEC isolates compared with non-ExPEC isolates (median ISS, 4.3 vs. 2.7: p = 0.03). In contrast, most individual VGs, VG scores, VG profiles, and virotypes were not associated with mouse virulence. Conclusions: ST131 subclone and ExPEC status, but not individual VGs, VG scores or profiles, or virotypes, predicted mouse virulence. Given the lower virulence of non-Rx H30 isolates, hyper-virulence probably cannot explain the ST131-H30 clade's epidemic emergence

Clinical and Economic Impact of Community-Onset Urinary Tract Infections Caused by ESBL-Producing Klebsiella pneumoniae Requiring Hospitalization in Spain : An Observational Cohort Study

Objective : To analyze the clinical and economic impact of community-onset urinary tract infections (UTIs) caused by extended-spectrum beta-lactamase (ESBL)-producing Klebsiella pneumoniae requiring hospitalization. Methods : A retrospective cohort study that included all adults with a UTI caused by K. pneumoniae that were admitted to a tertiary care hospital in Barcelona, Spain, between 2011 and 2015. Demographic, clinical, and economic data were analyzed. Results : One hundred and seventy-three episodes of UTIs caused by K. pneumoniae were studied; 112 were non-ESBL-producing and 61 were ESBL-producing. Multivariate analysis identified ESBL production, acute confusional state associated with UTI, shock, and the time taken to obtain adequate treatment as risk factors for clinical failure during the first seven days. An economic analysis showed differences between ESBL-producing and non-ESBL-producing K. pneumoniae for the total cost of hospitalization per episode (mean EUR 6718 vs EUR 3688, respectively). Multivariate analysis of the higher costs of UTI episodes found statistically significant differences for ESBL production and the time taken to obtain adequate treatment. Conclusion : UTIs caused by ESBL-producing K. pneumoniae requiring hospitalization and the time taken to obtain adequate antimicrobial therapy are associated with worse clinical and economic outcomes

A Phase 3 Study to Compare Delafloxacin With Moxifloxacin for the Treatment of Adults With Community-Acquired Bacterial Pneumonia (DEFINE-CABP)

The clinical and economic burden of community-acquired bacterial pneumonia (CABP) is significant and is anticipated to increase as the population ages and pathogens become more resistant. Delafloxacin is a fluoroquinolone antibiotic approved in the United States for the treatment of adults with acute bacterial skin and skin structure infections. Delafloxacin's shape and charge profile uniquely impact its spectrum of activity and side effect profile. This phase 3 study compared the efficacy and safety of delafloxacin with moxifloxacin for the treatment of CABP. A randomized, double-blind, comparator-controlled, multicenter, global phase 3 study compared the efficacy and safety of delafloxacin 300 mg twice daily or moxifloxacin 400 mg once daily in adults with CABP. The primary end point was early clinical response (ECR), defined as improvement at 96 (±24) hours after the first dose of study drug. Clinical response at test of cure (TOC) and microbiologic response were also assessed. In the intent-to-treat analysis population (ITT), ECR rates were 88.9% in the delafloxacin group and 89.0% in the moxifloxacin group. Noninferiority of delafloxacin compared with moxifloxacin was demonstrated. At TOC in the ITT population, the success rates were similar between groups. Treatment-emergent adverse events that were considered at least possibly related to the study drug occurred in 65 subjects (15.2%) in the delafloxacin group and 54 (12.6%) in the moxifloxacin group. Intravenous/oral delafloxacin monotherapy is effective and well tolerated in the treatment of adults with CABP, providing coverage for Gram-positive, Gram-negative, and atypical pathogens. NCT03534622. This Phase-3 study showed IV/oral delafloxacin monotherapy is well tolerated without QT restrictions or major drug interactions and effective in treatment of adults with CABP due to gram positive and negative as well as atypical pathogens

Relationship Between Biofilm Formation and Antimicrobial Resistance in Gram-Negative Bacteria

Gram-negative microorganisms are a significant cause of infection in both community and nosocomial settings. The increase, emergence, and spread of antimicrobial resistance among bacteria are the most important health problems worldwide. One of the mechanisms of resistance used by bacteria is biofilm formation, which is also a mechanism of virulence. This study analyzed the possible relationship between antimicrobial resistance and biofilm formation among isolates of three Gram-negative bacteria species. Several relationships were found between the ability to form biofilm and antimicrobial resistance, being different for each species. Indeed, gentamicin and ceftazidime resistance was related to biofilm formation in Escherichia coli, piperacillin/tazobactam, and colistin in Klebsiella pneumoniae, and ciprofloxacin in Pseudomonas aeruginosa. However, no relationship was observed between global resistance or multidrug-resistance and biofilm formation. In addition, compared with other reported data, the isolates in the present study showed higher rates of antimicrobial resistance. In conclusion, the acquisition of specific antimicrobial resistance can compromise or enhance biofilm formation in several species of Gram-negative bacteria. However, multidrug-resistant isolates do not show a trend to being greater biofilm producers than non-multiresistant isolates