Synergistic efficacy of ceftazidime/avibactam and aztreonam against carbapenemase-producing Pseudomonas aeruginosa: insights from the hollow-fiber infection model.

BACKGROUND: Combination therapy is an attractive therapeutic option for extensively drug-resistant (XDR) Pseudomonas aeruginosa infections. Existing data support the combination of aztreonam and ceftazidime/avibactam (CZA) against class serine-ß-lactamase (SBL)- and metallo-ß-lactamase (MBL) - producing Enterobacterales. However, data about that combination against SBL- and MBL-producing P. aeruginosa are scarce. The objective of the study was to assess the in vitro activity of CZA and aztreonam alone and in combination against SBL- and MBL-producing XDR P. aeruginosa isolates. METHODS: The combination was analyzed by means of the hollow-fiber infection model in three selected carbapenemase-producing P. aeruginosa isolates that were representative of the three most common XDRP. aeruginosa high-risk clones (ST175, ST111, ST235) responsible for global nosocomial infection outbreaks. RESULTS: The three isolates were nonsusceptible to CZA and nonsusceptible to aztreonam. In the dynamic hollow-fiber infection model, the combination of CZA plus aztreonam exerts a bactericidal effect on the isolates, regardless of their resistance mechanism and demonstrates synergistic interactions against three isolates, achieving a bacterial reduction of 5.07 log10 CFU/ml, 5.2 log10 CFU/ml and 4 log10 CFU/ml, respectively. CONCLUSION: The combination of CZA and aztreonam significantly enhanced the in vitro efficacy against XDR P. aeruginosa isolates compared to each monotherapy. This improvement suggests that the combination could serve as a feasible treatment alternative for infections caused by carbapenemase-producing XDR P. aeruginosa, especially in scenarios where no other treatment options are available.

New Predictive Equation for the Estimation of Plasma Concentrations of Formed Colistin in Patients Treated With Colistimethate Sodium for Multidrug-Resistant Gram-Negative Bacterial Infections.

BACKGROUND: The clinical use of colistin methanesulphonate (CMS) is limited by potential nephrotoxicity. The selection of an efficient and safe CMS dose for individual patients is complicated by the narrow therapeutic window and high interpatient pharmacokinetic variability. In this study, a simple predictive equation for estimating the plasma concentration of formed colistin in patients with multidrug and extremely drug-resistant gram-negative bacterial infections was developed. METHODS: The equation was derived from the largest clinical cohort of patients undergoing therapeutic drug monitoring (TDM) of colistin for over 8 years in a tertiary Spanish hospital. All variables associated with C ss,avg were selected in a multiple linear regression model that was validated in a second cohort of 40 patients. Measured C ss,avg values were compared with those predicted by our model and a previous published algorithm for critically ill patients. RESULTS: In total, 276 patients were enrolled [the mean age was 67.2 (13.7) years, 203 (73.6%)] were male, and the mean (SD) C ss,avg was 1.12 (0.98) mg/L. Age, gender, estimated glomerular filtration rate, CMS dose and frequency, and concomitant drugs were included in the model. In the external validation, the previous algorithm appeared to yield more optimized colistin plasma concentrations when all types of C ss,avg values (high and low) were considered, while our equation yielded a more optimized prediction in the subgroup of patients with low colistin plasma concentrations (C ss,avg <1.5 mg/L). CONCLUSIONS: The proposed equation may help clinicians to better use CMS among a wide variety of patients, to maximize efficacy and prevent nephrotoxicity. A further prospective PK study is warranted to externally validate this algorithm.

Colistin plasma concentrations are not associated with better clinical outcomes in patients with pneumonia caused by extremely drug-resistant Pseudomonas aeruginosa.

IMPORTANCE: In some cases, colistin is the only treatment option for infections caused by the very drug-resistant Pseudomonas aeruginosa. However, in the past decade, there have been questions concerning its pharmacokinetics and concentration at the site of infection. In this scenario, its use in a difficult-to-treat infection like pneumonia is currently debatable. This is a clinical pharmacokinetic study of colistin in patients with multidrug-resistant P. aeruginosa pneumonia. Our findings demonstrate that colistin exposure is associated with worse clinical outcomes rather than better clinical outcomes, implying that other therapeutic options should be explored in this clinical setting.

Changes in Group A Streptococcus emm Types Associated with Invasive Infections in Adults, Spain, 2023.

An increase in invasive group A Streptococcus infection was detected in the northeast of Spain in November 2022. A postpandemic decline in the diversity of circulating emm types involved in invasive group A Streptococcus was observed, along with the emergence of emm49 in this geographic area.

Ampicillin-resistant and vancomycin-susceptible Enterococcus faecium bacteremia: a clinical narrative review.

INTRODUCTION: Enterococcus faecium is a commensal microorganism that can cause infections such as bacteremia. Incidence of ampicillin-resistant and vancomycin-susceptible E. faecium (EfARSV) bacteremia is on the rise, and the mortality rate is high. Despite much data, the most appropriate treatment remains a question. AREAS COVERED: This article mostly reviews the relevant aspects of EfARSV bacteremia: microbiology, gastrointestinal tract colonization and invasion, antibiotic resistance, epidemiology, risk factors, mortality, and treatment, including pharmacologic components of employed agents and related clinical evidence. A literature search was conducted on PubMed on 31 July 2022, which was updated on 15 November 2022. EXPERT OPINION: EfARSV bacteremia presents high mortality. However, it is uncertain whether mortality is attributable to or a marker of severity/comorbidities. Considering its antibiotic resistance pattern, EfARSV is considered a difficult-to-treat microorganism. Glycopeptides have been used to treat EfARSV, with linezolid and daptomycin serving as potential alternative agents. Yet, the use of daptomycin is controversial due to a higher risk of treatment failures. Clinical evidence on this issue is scarce, unfortunately, and subject to many limitations. Despite increased incidence and mortality, EfARSV bacteremia presents multiple aspects to be addressed in well-conducted studies.

Antibiotic Susceptibility and Clarithromycin Resistance Determinants in Helicobacter pylori in the Northeast of Spain: A One-Year Prospective Study.

Helicobacter pylori is one of the most widespread infections, and it is reaching alarming resistance levels worldwide. The recommended first-line empirical treatment differs according to the local rate of clarithromycin resistance. Macrolide resistance is mainly associated with three point mutations in the 23S rRNA gene. The aim of this study was to describe the antibiotic susceptibility of H. pylori in our healthcare area and the main mechanisms involved in clarithromycin resistance. Gastric biopsies (n = 641) were collected and cultured in a one-year prospective study. Antibiotic susceptibility testing was performed by gradient diffusion. A multiplex real-time PCR test (AllplexTMH.pylori & ClariR Assay, Seegene) was used to detect the most frequent mutations associated with clarithromycin resistance. Overall, 141 isolates were available for antibiotic susceptibility testing. The highest resistance rates were detected in metronidazole and levofloxacin. The rate of clarithromycin resistance was 12.1%, and the associated mutations were A2143G and A2142G. More than half of the clarithromycin-resistant isolates presented high MIC values (>256 mg/L). Tetracycline resistance was not detected, suggesting that therapies that contain tetracycline could be a suitable option. The low clarithromycin resistance rate coupled with the high rates of metronidazole resistance may support the recovery of the classical triple therapy in our healthcare area.

Minimal number of cultures needed to detect Cutibacterium acnes in primary reverse shoulder arthroplasty: a prospective study.

BACKGROUND: The objective of this study was to determine the minimum number of cultures needed to detect Cutibacterium acnes in primary reverse shoulder arthroplasties (RSAs). METHODS: It is a prospective study including 160 primary RSAs. Exclusion criteria included an active infection, an invasive shoulder treatment in the last 6 months before surgery, an Arthro-SCAN or Arthro-MRI in the last 6 months before surgery, previous shoulder surgeries and revision cases. In 90 cases, 11 cultures were obtained. Another 10 cultures were obtained in the other 70 cases (culture 10 was a sterile sponge to detect false positives). To determine the minimum number of cultures needed to detect C acnes, the prevalence of C acnes contamination of the 160 patients included was determined. RESULTS: There were 128 females and 32 males, with a mean age of 74 years. There were 1690 cultures obtained from the 160 primary RSA surgeries, and 132 of them turned out to be positive for C acnes. There were 42 patients with positive cultures. Twenty of them were males and 22 females. When considering the skin and the deep tissue cultures altogether, the prevalence of positive cultures for C acnes was of 26.25%. If only deep tissues cultures were considered, the prevalence of positive cultures for C acnes was of 23.13%. When considering the skin and the deep tissue cultures together, the sensitivity to detect the C acnes is 19% if only 1 culture is obtained, 31% if 2 cultures are obtained, 50% if 3 cultures are obtained, 59.5% if 4 cultures are obtained, 66.7% if 5 cultures are obtained, 73.8% if 6 cultures are obtained, 85.7% if 7 cultures are obtained, and 92.9% if 8 cultures are obtained. When considering only the deep tissue cultures, if only 1 culture is obtained, the sensitivity to detect the C acnes is 24.3%, 40.5% if 2 cultures are obtained, 54.1% if 3 cultures are obtained, 73% if 4 cultures are obtained, 89.2% if 5 cultures are obtained, and 97.3% if 6 or 7 cultures are obtained. DISCUSSION: A minimum number of 8 cultures are needed to detect C acnes in skin. Moreover, a minimum of 6 cultures are needed to detect it in deep tissues when performing an RSA.

Suboptimal Concentrations of Ceftazidime/Avibactam (CAZ-AVI) May Select for CAZ-AVI Resistance in Extensively Drug-Resistant Pseudomonas aeruginosa: In Vivo and In Vitro Evidence.

This study correlates in vivo findings in a patient with an extensively drug-resistant (XDR) P. aeruginosa infection who developed resistance to ceftazidime-avibactam (CAZ-AVI) with in vitro results of a 7-day hollow-fiber infection model (HFIM) testing the same bacterial strain. The patient was critically ill with ventilator-associated pneumonia caused by XDR P. aeruginosa ST175 with CAZ-AVI MIC of 6 mg/L and was treated with CAZ-AVI in continuous infusion at doses adjusted for renal function. Plasma concentrations of CAZ-AVI were analyzed on days 3, 7, and 10. In the HIFM, the efficacy of different steady-state concentrations (Css) of CAZ-AVI (12, 18, 30 and 48 mg/L) was evaluated. In both models, a correlation was observed between the decreasing plasma levels of CAZ-AVI and the emergence of resistance. In the HIFM, a Css of 30 and 48 mg/L (corresponding to 5× and 8× MIC) had a bactericidal effect without selecting resistant mutants, whereas a Css of 12 and 18 mg/L (corresponding to 2× and 3× MIC) failed to prevent the emergence of resistance. CAZ/AVI resistance development was caused by the selection of a single ampC mutation in both patient and HFIM. Until further data are available, strategies to achieve plasma CAZ-AVI levels at least 4× MIC could be of interest, particularly in severe and high-inoculum infections caused by XDR P. aeruginosa with high CAZ-AVI MICs.

Comparative Analysis of Complicated Urinary Tract Infections Caused by Extensively Drug-Resistant Pseudomonas aeruginosa and Extended-Spectrum ß-Lactamase-Producing Klebsiella pneumoniae.

The objective was to compare clinical characteristics, outcomes, and economic differences in complicated urinary tract infections (cUTI) caused by extensively drug-resistant Pseudomonas aeruginosa (XDR P. aeruginosa) and extended-spectrum beta-lactamase-producing Klebsiella pneumoniae (ESBL-K. pneumoniae). A retrospective study was conducted at a tertiary care hospital. Patients with XDR P. aeruginosa and ESBL-K. pneumoniae cUTIs were compared. The primary outcome was clinical failure at day 7 and at the end of treatment (EOT). Secondary outcomes: 30- and 90-day mortality, microbiological eradication, and economic cost. Two-hundred and one episodes were included, of which 24.8% were bloodstream infections. Patients with XDR P. aeruginosa cUTI more frequently received inappropriate empirical therapy (p < 0.001). Nephrotoxicity due to antibiotics was only observed in the XDR P. aeruginosa group (26.7%). ESBL-K. pneumoniae cUTI was associated with worse eradication rates, higher recurrence, and higher infection-related readmission. In multivariate analysis, XDR P. aeruginosa was independently associated with clinical failure on day 7 of treatment (OR 4.34, 95% CI 1.71−11.04) but not at EOT, or with mortality. Regarding hospital resource consumption, no significant differences were observed between groups. XDR P. aeruginosa cUTI was associated with worse early clinical cures and more antibiotic side effects than ESBL-K. pneumoniae infections. However, no differences in mortality or in hospitalization costs were observed.

ATP Bioluminescence Assay To Evaluate Antibiotic Combinations against Extensively Drug-Resistant (XDR) Pseudomonas aeruginosa.

Time-kill curves are used to study antibiotic combinations, but the colony count method to obtain the results is time-consuming. The aim of the study was to validate an ATP assay as an alternative to the conventional colony count method in studies of antibiotic combinations. The cutoff point for synergy and bactericidal effect to categorize the results using this alternative method were determined in Pseudomonas aeruginosa. The ATP assay was performed using the GloMax 96 microplate luminometer (Promega), which measures bioluminescence in relative light units (RLU). To standardize this assay, background, linearity, and the detection limit were determined with one strain each of multidrug-resistant P. aeruginosa and Klebsiella pneumoniae. Twenty-four-hour time-kill curves were performed in parallel by both methods with 12 strains of P. aeruginosa. The conventional method was used as a "gold" standard to establish the pharmacodynamic cutoff points in the ATP method. Normal saline solution was established as washing/dilution medium. RLU signal correlated with CFU when the assay was performed within the linear range. The categorization of the pharmacodynamic parameters using the ATP assay was equivalent to that of the colony count method. The bactericidal effect and synergy cutoff points were 1.348 (93% sensitivity, 81% specificity) and 1.065 (95% sensitivity, 89% specificity) log RLU/mL, respectively. The ATP assay was useful to determine the effectiveness of antibiotic combinations in time-kill curves. This method, less laborious and faster than the colony count method, could be implemented in the clinical laboratory workflow. IMPORTANCE Combining antibiotics is one of the few strategies available to overcome infections caused by multidrug-resistant bacteria. Time-kill curves are usually performed to evaluate antibiotic combinations, but obtaining results is too laborious to be routinely performed in a clinical laboratory. Our results support the utility of an ATP measurement assay using bioluminescence to determine the effectiveness of antibiotic combinations in time-kill curves. This method may be implemented in the clinical laboratory workflow as it is less laborious and faster than the conventional colony count method. Shortening the obtention of results to 24 h would also allow an earlier guided combined antibiotic treatment.

Scientific evidence of the duration of antibiotic treatment in intra-abdominal infections with surgical focus control.

A non-systematic review of the published scientific evidence has been carried out on the duration of empirical antibiotic treatment in surgical intra-abdominal infections (IIA) with effective focus control. Given the progressive increase in antibiotic resistance, it is urgent to have strategies to reduce the pressure on the microbiota. The American guidelines made by Mazuski et al. of 20171, as the central axis in the recommendations of the duration of empirical antibiotic treatment in intra-abdominal infections with control of the focus and a bibliographic search of all the articles that contained the keywords in Pubmed and Google Scholar is added. 21 articles referring to the duration of empirical antibiotic treatment in intra-abdominal infection with control of the focus are collected. With the American guidelines and these articles, a proposal is prepared for the duration of empirical antibiotic treatment in patients without risk factors between 24 and 72 h. And in those who present risk factors, it should be individualized with active monitoring every 24 h of fever, paralytic ileus and leukocytosis (FIL), before an early detection of complications or the need for changes in antibiotic treatment. Short treatments are just as effective as those of longer durations and are associated with fewer adverse effects, therefore, daily adjusting and reassessing the duration of empirical antibiotic treatment is essential for better practice.

Comparison of Ceftolozane/Tazobactam Infusion Regimens in a Hollow-Fiber Infection Model against Extensively Drug-Resistant Pseudomonas aeruginosa Isolates.

The aim of this study was to compare the efficacy of intermittent (1-h), extended (4-h), and continuous ceftolozane-tazobactam (C/T) infusion against three extensively drug-resistant (XDR) sequence type (ST) 175 P. aeruginosa isolates with different susceptibilities to C/T (MIC = 2 to 16 mg/L) in a 7-day hollow-fiber infection model (HFIM). C/T in continuous infusion achieved the largest reduction in total number of bacterial colonies in the overall treatment arms for both C/T-susceptible and -resistant isolates. It was also the only regimen with bactericidal activity against all three isolates. These data suggest that continuous C/T infusion should be considered a potential treatment for infections caused by XDR P. aeruginosa isolates, including nonsusceptible ones. Proper use of C/T dosing regimens may lead to better clinical management of XDR P. aeruginosa infections. IMPORTANCE Ceftolozane-tazobactam (C/T) is an antipseudomonal antibiotic with a high clinical impact in treating infection caused by extensively drug-resistant (XDR) Pseudomonas aeruginosa isolates, but resistance is emerging. Given its time-dependent behavior, C/T continuous infusion can improve exposure and therefore the pharmacokinetic/pharmacodynamic target attainment. We compared the efficacy of intermittent, extended, and continuous C/T infusion against three XDR ST175 P. aeruginosa isolates with different C/T MICs by means of an in vitro dynamic hollow-fiber model. We demonstrated that C/T in continuous infusion achieved the largest reduction in bacterial density in the overall treatment arms for both susceptible and resistant isolates. It was also the only regimen with bactericidal activity against all three isolates. Through this study, we want to demonstrate that developing individually tailored antimicrobial treatments is becoming essential. Our results support the role of C/T level monitoring and of dose adjustments for better clinical management and outcomes.

Prevalence and seasonality of viral respiratory infections in a temperate climate region: A 24-year study (1997-2020).

BACKGROUND: Few long-term reports have been published on the epidemiology of respiratory viruses despite their frequent involvement in extremely common infections. The aim here was to determine the frequency and distribution of respiratory viruses in a temperate climate area (Barcelona, Spain) throughout a 24-year period. METHODS: We collected data on all respiratory viruses detected from 1997 to 2020 in our institution. Clinical specimens were analyzed mainly by conventional techniques, and molecular techniques were also used. RESULTS: Of the 59,579 specimens analyzed, 21,382 (35.9%) were positive for at least one virus. The number of positive samples during cold months was significantly higher than in warm months. Respiratory virus infections were detected in patients of all ages, above all in children under 3 years of age, who were most frequently infected with the respiratory syncytial virus, whereas Influenza A virus predominated in the other groups, especially in adults. A clear demographic and seasonal pattern was established for some viruses. Circulation of other respiratory viruses during the FLUAV H1N1pdm09 and SARS-CoV-2 pandemics was observed. CONCLUSIONS: This long-term study provides new knowledge about the prevalence of respiratory viruses in a Mediterranean region. Throughout the study period, the frequency of some viruses remained constant, whereas others varied with the year. A clear demographic and seasonal pattern was established for some viruses. Patients suffering from severe respiratory infections should be examined for a range of respiratory viruses regardless of gender, age, or season.

Aminoglycoside or Polymyxin Monotherapy for Treating Complicated Urinary Tract Infections Caused by Extensively Drug-Resistant Pseudomonas aeruginosa: A Propensity Score-Adjusted and Matched Cohort Study.

INTRODUCTION: Extensively drug-resistant (XDR) Pseudomonas aeruginosa (PA) infections are difficult to treat. We aimed to compare aminoglycosides or polymyxin monotherapy versus other antibiotic regimens (carbapenems, aztreonam, ceftazidime, cefepime, ceftolozane-tazobactam, or ceftazidime-avibactam) in complicated urinary tract infections (cUTI) caused by XDR-PA. METHODS: Study performed at a tertiary-care hospital from 2010 to 2019. All consecutive adult patients with XDR-PA urine cultures and diagnosed with cUTI were retrospectively reviewed. XDR phenotype was defined according to Magiorakos et al. A propensity score was used as a covariate in multivariate analyses and for matching. Primary outcome was early clinical failure and at end of treatment (EOT). Main secondary outcomes were 30- and 90-day mortality, microbiological clearance, and antibiotic-related side effects. RESULTS: Of the 465 episodes screened, 101 were included, 48% were treated with aminoglycoside or colistin monotherapy. Most XDR-PA were susceptible to colistin (100%) and amikacin (43%). Patients treated with antibiotic regimens other than aminoglycosides or polymyxin monotherapy were more likely to have hematologic malignancy (p < 0.001), higher SOFA score (p = 0.048), and bacteremia (p = 0.003). In multivariate models adjusted by propensity score, aminoglycoside or colistin monotherapy was not associated with worse outcomes. After propensity score matching, 28 episodes in each treatment group were matched. Adjusted ORs (95% CI) for early clinical failure and at EOT with aminoglycosides or polymyxin monotherapy were 0.53 (0.18-1.58) and 1.29 (0.34-4.83), respectively. Aminoglycoside or colistin monotherapy was not associated with higher 30-day (HR 0.93, 95% CI 0.17-5.08) or 90-day mortality (HR 0.68, 95% CI 0.20-2.31), nor with absence of microbiological clearance (OR 0.72, 95% CI 0.33-1.58). No statistically significant differences were found in terms of nephrotoxicity. Clostridioides difficile infection was observed only in the "other antibiotic regimens" group (n = 6, 11.3%). CONCLUSIONS: Aminoglycosides or polymyxin monotherapy showed good efficacy and safety profile in treating cUTI caused by XDR-PA. These results may be useful for antibiotic stewardship activities.

Are Cutibacterium acnes present at the end of primary shoulder prosthetic surgeries responsible for infection? Prospective study.

The purpose of this study was to investigate if the C. acnes present at the end of a primary shoulder arthroplasty could be responsible for shoulder arthroplasty infection. Prospective study includes patients undergoing primary shoulder arthroplasty from January 2015 until December 2018. From all the patients included, 5 to 12 tissue samples were obtained and were specifically cultured to detect the presence of C. acnes. DNA was extracted from the C acnes isolated colonies and Whole Genome Sequencing (WGS) analysis was done. A cohort of 156 patients was finally included. In twenty-seven patients, the C. acnes was present at the end of the primary surgery. Two of these patients developed a C. acnes periprosthetic shoulder infection at 6 and 4 months after the primary surgery. WGS of C. acnes isolated colonies showed that all the revision-surgery isolates clustered near to the corresponding primary-surgery isolates compared to the other independent bacterial colonies. (99.89% of similarity). C. acnes present at the end of the primary surgery can be the cause of early or delayed periprosthetic joint infections in shoulder arthroplasty.

Impact of ceftolozane/tazobactam concentrations in continuous infusion against extensively drug-resistant Pseudomonas aeruginosa isolates in a hollow-fiber infection model.

Ceftolozane/tazobactam (C/T) has emerged as a potential agent for the treatment of extensively drug-resistant (XDR) Pseudomonas aeruginosa infections. As it is a time-dependent antimicrobial, prolonged infusion may help achieve pharmacokinetic/pharmacodynamic (PK/PD) targets. To compare alternative steady-state concentrations (Css) of C/T in continuous infusion (CI) against three XDR P. aeruginosa ST175 isolates with C/T minimum inhibitory concentration (MIC) values of 2 to 16 mg/L in a hollow-fiber infection model (HFIM). Duplicate 10-day HFIM assays were performed to evaluate Css of C/T in CI: one compared 20 and 45 mg/L against the C/T-susceptible isolate while the other compared 45 and 80 mg/L against the two C/T-non-susceptible isolates. C/T resistance emerged when C/T-susceptible isolate was treated with C/T in CI at a Css of 20 mg/L; which showed a deletion in the gene encoding AmpC ß-lactamase. The higher dosing regimen (80 mg/L) showed a slight advantage in effectiveness. The higher dosing regimen has the greatest bactericidal effect, regardless of C/T MIC. Exposure to the suboptimal Css of 20 mg/L led to the emergence of C/T resistance in the susceptible isolate. Antimicrobial regimens should be optimized through C/T levels monitoring and dose adjustments to improve clinical management.

Daptomycin versus Glycopeptides for the Treatment of Enterococcus faecium Bacteraemia: A Cohort Study.

BACKGROUND: Ampicillin resistant and glycopeptide susceptible Enterococcus faecium bloodstream infection (GSEF-BSI) incidence has risen. However, the treatment of choice remains unknown. Daptomycin use for the treatment of enterococcal infections has increased, despite effectiveness and safety concerns. The objective was to compare the effectiveness and safety of daptomycin and glycopeptides in the treatment of GSEF-BSI. METHODS: This was a single-centre, retrospective observational cohort study performed at Hospital del Mar (Barcelona, Spain), from January 2006-May 2018. The primary outcome was clinical cure at the end of the therapy, and secondary outcomes included 14-day, 30-day, in-hospital mortality, and length of stay. RESULTS: From a total of 192 patients with GSEF-BSI, 54 (28.1%) were treated with glycopeptides and 17 (8.9%) with daptomycin. Patients treated with daptomycin presented a lower clinical cure than patients treated with glycopeptides (58.8% vs. 83.3%, RR 0.416 (95% CI 0.189-0.915)). After controlling for confounding variables by means of multivariate analysis the significative difference was confirmed (aOR 4.313, 95% CI, 1.053-17.660). The need for treatment discontinuation due to adverse events was similar. CONCLUSIONS: Patients with GSEF-BSI treated with glycopeptides showed a higher clinical cure than those treated with daptomycin.

Time-Kill Evaluation of Antibiotic Combinations Containing Ceftazidime-Avibactam against Extensively Drug-Resistant Pseudomonas aeruginosa and Their Potential Role against Ceftazidime-Avibactam-Resistant Isolates.

Ceftazidime-avibactam (CZA) has emerged as a promising solution to the lack of new antibiotics against Pseudomonas aeruginosa infections. Data from in vitro assays of CZA combinations, however, are scarce. The objective of our study was to perform a time-kill analysis of the effectiveness of CZA alone and in combination with other antibiotics against a collection of extensively drug-resistant (XDR) P. aeruginosa isolates. Twenty-one previously characterized representative XDR P. aeruginosa isolates were selected. Antibiotic susceptibility was tested by broth microdilution, and results were interpreted using CLSI criteria. The time-kill experiments were performed in duplicate for each isolate. Antibiotics were tested at clinically achievable free-drug concentrations. Different treatment options, including CZA alone and combined with amikacin, aztreonam, meropenem, and colistin, were evaluated to identify the most effective combinations. Seven isolates were resistant to CZA (MIC ≥ 16/4 mg/liter), including four metallo-ß-lactamase (MBL)-carrying isolates and two class A carbapenemases. Five of them were resistant or intermediate to aztreonam (MIC ≥ 16 mg/liter). Three isolates were resistant to amikacin (MIC ≥ 64 mg/liter) and one to colistin (MIC ≥ 4 mg/liter). CZA monotherapy had a bactericidal effect in 100% (14/14) of the CZA-susceptible isolates. Combination therapies achieved a greater overall reduction in bacterial load than monotherapy for the CZA-resistant isolates. CZA plus colistin was additive or synergistic in 100% (7/7) of the CZA-resistant isolates, while CZA plus amikacin and CZA plus aztreonam were additive or synergistic in 85%. CZA combined with colistin, amikacin, or aztreonam was more effective than monotherapy against XDR P. aeruginosa isolates. A CZA combination could be useful for treating XDR P. aeruginosa infections, including those caused by CZA-resistant isolates. IMPORTANCE The emergence of resistance to antibiotics is a serious public health problem worldwide and can be a cause of mortality. For this reason, antibiotic treatment is compromised, and we have few therapeutic options to treat infections. The main goal of our study is to search for new treatment options for infections caused by difficult-to-treat resistant germs. Pseudomonas aeruginosa is a Gram-negative bacterium distributed throughout the world with the ability to become resistant to most available antibiotics. Ceftazidime-avibactam (CZA) emerged as a promising solution to the lack of new antibiotics against infections caused by P. aeruginosa strains. This study intended to analyze the effect of CZA alone or in combination with other available antibiotics against P. aeruginosa strains. The combination of CZA with other antibiotics could be more effective than monotherapy against extensively drug-resistant P. aeruginosa strains.

Risk Factors for Amoxicillin-Clavulanate Resistance in Community-Onset Urinary Tract Infections Caused by Escherichia coli or Klebsiella pneumoniae: The Role of Prior Exposure to Fluoroquinolones.

BACKGROUND: High rates of amoxicillin-clavulanate (AMC) resistance among Enterobacterales isolated from urinary tract infections (UTIs) were observed in our area. The aim of this study was to identify risk factors associated with AMC resistance in patients with community-onset UTI in emergency departments (EDs). METHODS: A retrospective study was performed of all ED patients with positive urine cultures for Escherichia coli or Klebsiella pneumoniae in a Spanish tertiary-care hospital. RESULTS: 330 urine cultures in all were included: 261 (79.1%) for E. coli and 69 (20.90%) for K. pneumonia. Rates of AMC resistance were 14.94% and 34.78%, respectively. UTI was clinically confirmed in 212 (64.24%) cases. Previous antimicrobial exposure was independently associated with AMC resistance development in E. coli and K. pneumoniae urinary isolates (OR = 2.94, 95% CI = 1.55-5.58). Analyses of infected patients revealed that previous exposure to fluoroquinolones (OR = 3.33, 95% CI = 1.10-10.12, p = 0.034) and to AMC (OR = 5.68, 95% CI = 1.97-16.44, p = 0.001) was significantly associated with isolation of AMC-resistant strains. CONCLUSIONS: Prior antibiotic exposure, particularly to AMC or fluoroquinolones, was the only independent risk factor associated with development of AMC resistance in E. coli and K. pneumoniae urinary isolates from patients attending the ED.

Risk Factors for Mortality among Patients with Pseudomonas aeruginosa Bloodstream Infections: What Is the Influence of XDR Phenotype on Outcomes?

This study aimed to assess the impact of extensively drug-resistant (XDR) phenotype on mortality in Pseudomonas aeruginosa bacteremia. A retrospective cohort study was performed in a tertiary hospital from January 2000 to December 2018. All consecutive prospectively recorded P. aeruginosa bacteremia in adult patients were assessed. In this study, 382 patients were included, of which 122 (31.9%) due to XDR P. aeruginosa. Independent factors associated with 14-day mortality were as follows: high-risk source of bacteremia (hazard ratio (HR) 3.07, 95% confidence interval (CI), 1.73-5.46), septic shock (HR 1.75, 95% CI, 1.12-2.75), and higher Pitt scores (one-point increments; HR 1.25, 95% CI, 1.12-1.38). Otherwise, the appropriateness of definitive antibiotic therapy was a protective factor (HR 0.39, 95% CI, 0.24-0.62). The same variables were also associated with 30-day mortality. XDR phenotype was not associated with 14- or 30-day mortality. In a subanalysis considering only high-risk source cases, combined antimicrobial therapy was independently associated with 14-day favorable outcome (HR 0.56, 95% CI, 0.33-0.93). In conclusion, XDR phenotype was not associated with poor prognosis in patients with P. aeruginosa bacteremia in our cohort. However, source of infection, clinical severity, and inappropriate definitive antibiotic therapy were risk factors for mortality. Combined antimicrobial therapy should be considered for high-risk sources.