Efficacy of cefiderocol- vs colistin-containing regimen for treatment of bacteraemic ventilator-associated pneumonia caused by carbapenem-resistant Acinetobacter baumannii in patients with COVID-19.

INTRODUCTION: Ventilator-associated pneumonia (VAP) caused by carbapenem-resistant Acinetobacter baumannii (CRAB) in patients hospitalized in intensive care units (ICUs) is an important and challenging complication, including in patients with coronavirus disease 2019 (COVID-19). Considering the poor lung penetration of most antibiotics, including intravenous colistin due to the poor pharmacokinetics/pharmacodynamics at the infection site, the choice of the best antibiotic regimen is still being debated. METHODS: This single-centre, observational study was conducted from March 2020 to August 2022, and included all patients hospitalized consecutively with VAP and concomitant bloodstream infection due to CRAB in the COVID-ICU. The main goal of the study was to evaluate risk factors associated with survival or death at 30 days from VAP onset. A propensity score for receiving therapy was added to the model. RESULTS: During the study period, 73 patients who developed VAP and concomitant positive blood cultures caused by CRAB were enrolled in the COVID-ICU. Of these patients, 67 (91.7%) developed septic shock, 42 (57.5%) had died at 14 days and 59 (80.8%) had died at 30 days. Overall, 54 (74%) patients were treated with a colistin-containing regimen and 19 (26%) were treated with a cefiderocol-containing regimen. Cox regression analysis showed that chronic obstructive pulmonary disease and age were independently associated with 30-day mortality. Conversely, cefiderocol-containing regimens and cefiderocol + fosfomycin in combination were independently associated with 30-day survival, as confirmed by propensity score analysis. CONCLUSIONS: This real-life study in patients with bacteraemic VAP caused by CRAB provides useful suggestions for clinicians, showing a possible benefit of cefiderocol and its association with fosfomycin.

Early initiation of three-drug combinations for the treatment of carbapenem-resistant A. baumannii among COVID-19 patients.

OBJECTIVES: We evaluated the clinical characteristics and outcomes of patients with COVID-19 who received three-drug combination regimens for treatment of carbapenem-resistant Acinetobacter baumannii (CRAB) infections during a single-centre outbreak. Our objective was to describe the clinical outcomes and molecular characteristics and in vitro synergy of antibiotics against CRAB isolates. MATERIALS AND METHODS: Patients with severe COVID-19 admitted between April and July 2020 with CRAB infections were retrospectively evaluated. Clinical success was defined as resolution of signs/symptoms of infection without need for additional antibiotics. Representative isolates underwent whole-genome sequencing (WGS) and in vitro synergy of two- or three-drug combinations was assessed by checkerboard and time-kill assays, respectively. RESULTS: Eighteen patients with CRAB pneumonia or bacteraemia were included. Treatment regimens included high-dose ampicillin-sulbactam, meropenem, plus polymyxin B (SUL/MEM/PMB; 72%), SUL/PMB plus minocycline (MIN; 17%) or other combinations (12%). Clinical resolution was achieved in 50% of patients and 30-day mortality was 22% (4/18). Seven patients had recurrent infections, during which further antimicrobial resistance to SUL or PMB was not evident. PMB/SUL was the most active two-drug combination by checkerboard. Paired isolates collected before and after treatment with SUL/MEM/PMB did not demonstrate new gene mutations or differences in the activity of two- or three-drug combinations. CONCLUSIONS: Use of three-drug regimens for severe CRAB infections among COVID-19 resulted in high rates of clinical response and low mortality relative to previous studies. The emergence of further antibiotic resistance was not detected phenotypically or through WGS analysis. Additional studies are needed to elucidate preferred antibiotic combinations linked to the molecular characteristics of infecting strains.

A carbapenem-focused antimicrobial stewardship programme implemented during the COVID-19 pandemic in a setting of high endemicity for multidrug-resistant Gram-negative bacteria.

BACKGROUND: Greece is among the countries characterized by high rates of antimicrobial resistance and high consumption of antibiotics, including carbapenems. OBJECTIVES: To measure the impact of a carbapenem-focused antimicrobial stewardship programme (ASP) on the antibiotic consumption and patient outcomes in a Greek tertiary hospital during the COVID-19 pandemic. METHODS: A quasi-experimental, before-after study, comparing a 12 month pre-intervention period with a 12 month intervention period in which a carbapenem-focused ASP was implemented. RESULTS: A total of 1268 patients were enrolled. The proportion of admitted patients who received carbapenems decreased from 4.1% (842 of 20 629) to 2.3% (426 of 18 245) (-1.8%; P < 0.001). A decrease of -4.9 DDD/100 patient-days (PD) (95% CI -7.3 to -2.6; P = 0.007) in carbapenem use and an increase in the use of piperacillin/tazobactam [+2.1 DDD/100 PD (95% CI 1.0-3.3; P = 0.010)] were observed. Thirty-day mortality following initiation of carbapenem treatment and all-cause in-hospital mortality remained unaltered after ASP implementation. In contrast, length of hospital stay increased (median 17.0 versus 19.0 days; P < 0.001), while the risk of infection-related readmission within 30 days of hospital discharge decreased (24.6% versus 16.8%; P = 0.007). In the post-implementation period, acceptance of the ASP intervention was associated with lower daily hazard of in-hospital death [cause-specific HR (csHR) 0.49; 95% CI 0.30-0.80], lower odds of 30 day mortality (OR 0.36; 95% CI 0.18-0.70) and higher rate of treatment success (csHR 2.45; 95% CI 1.59-3.77). CONCLUSIONS: Implementing and maintaining a carbapenem-focused ASP is feasible, effective and safe in settings with high rates of antimicrobial resistance, even during the COVID-19 pandemic.

Carbapenemase-Encoding Genes and Colistin Resistance in Gram-Negative Bacteria During the COVID-19 Pandemic in Mexico: Results from the Invifar Network.

In this study, we report the carbapenemase-encoding genes and colistin resistance in Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa in the second year of the COVID-19 pandemic. Clinical isolates included carbapenem-resistant K. pneumoniae, carbapenem-resistant E. coli, carbapenem-resistant A. baumannii, and carbapenem-resistant P. aeruginosa. Carbapenemase-encoding genes were detected by PCR. Carbapenem-resistant K. pneumoniae and carbapenem-resistant E. coli isolates were analyzed using the Rapid Polymyxin NP assay. mcr genes were screened by PCR. Pulsed-field gel electrophoresis and whole-genome sequencing were performed on representative isolates. A total of 80 carbapenem-resistant E. coli, 103 carbapenem-resistant K. pneumoniae, 284 carbapenem-resistant A. baumannii, and 129 carbapenem-resistant P. aeruginosa isolates were recovered. All carbapenem-resistant E. coli and carbapenem-resistant K. pneumoniae isolates were included for further analysis. A selection of carbapenem-resistant A. baumannii and carbapenem-resistant P. aeruginosa strains was further analyzed (86 carbapenem-resistant A. baumannii and 82 carbapenem-resistant P. aeruginosa). Among carbapenem-resistant K. pneumoniae and carbapenem-resistant E. coli isolates, the most frequent gene was blaNDM (86/103 [83.5%] and 72/80 [90%], respectively). For carbapenem-resistant A. baumannii, the most frequently detected gene was blaOXA-40 (52/86, 60.5%), and for carbapenem-resistant P. aeruginosa, was blaVIM (19/82, 23.2%). For carbapenem-resistant A. baumannii, five indistinguishable pulsotypes were detected. Circulation of K. pneumoniae New Delhi metallo-ß-lactamase (NDM) and E. coli NDM was detected in Mexico. High virulence sequence types (STs), such as K. pneumoniae ST307, E. coli ST167, P. aeruginosa ST111, and A. baumannii ST2, were detected. Among K. pneumoniae isolates, 18/101 (17.8%) were positive for the Polymyxin NP test (two, 11.0% positive for the mcr-1 gene, and one, 5.6% with disruption of the mgrB gene). All E. coli isolates were negative for the Polymyxin NP test. In conclusion, K. pneumoniae NDM and E. coli NDM were detected in Mexico, with the circulation of highly virulent STs. These results are relevant in clinical practice to guide antibiotic therapies considering the molecular mechanisms of resistance to carbapenems.

Large increase in bloodstream infections with carbapenem-resistant Acinetobacter species during the first 2 years of the COVID-19 pandemic, EU/EEA, 2020 and 2021.

Recent data from the European Antimicrobial Resistance Surveillance Network (EARS-Net) show a large increase of +57% in Acinetobacter species bloodstream infections in the European Union and European Economic Area in the first years of the COVID-19 pandemic (2020-2021) compared with 2018-2019. Most were resistant to carbapenems, from intensive care units, and in countries with ≥ 50% carbapenem resistance in Acinetobacter spp. in 2018-2019. This highlights the requirement for reinforced Acinetobacter preparedness and infection prevention and control in Europe.

Acquisition of carbapenem-resistant gram-negative bacilli among intensive care unit (ICU) patients with no previous use of carbapenems: Indirect population impact of antimicrobial use.

OBJECTIVE: To measure the impact of exposure to patients using carbapenem on the acquisition of carbapenem-resistant gram-negative bacilli (CR-GNB) among patients not using carbapenems. DESIGN: An ecological study and a cohort study. SETTING: Two medical surgical intensive care units (ICUs) in inner Brazil. PARTICIPANTS: Patients admitted to 2 ICUs from 2013 through 2018 to whom carbapenem was not prescribed. METHODS: In the ecologic study, the monthly use of carbapenems (days of therapy [DOT] per 1,000 patient days) was tested for linear correlation with the 2-month moving average of incidence CR-GNB among patients to whom carbapenem was not prescribed. In the cohort study, those patients were addressed individually for risk factors (demographics, invasive interventions, use of antimicrobials) for acquisition of CR-GNB, including time at risk and the "carbapenem pressure," described as the aggregate DOT among other ICU patients during time at risk. The analysis was performed in univariate and multivariable Poisson regression models. RESULTS: The linear regression model revealed an association of total carbapenem use and incidence of CR-GNB (coefficient, 0.04; 95% confidence interval [CI], 0.02-0.06; P = .001). In the cohort model, the adjusted rate ratio (RR) for carbapenem DOT was 1.009 (95% CI, 1.001-1.018; P = .03). Other significant risk factors were mechanical ventilation and the previous use of ceftazidime (with or without avibactam). CONCLUSIONS: Every additional DOT of total carbapenem use increased the risk of CR-GNB acquisition by patients not using carbapenems by nearly 1%. We found evidence for a population ("herd effect"-like) impact of antimicrobial use in the ICUs.

Predictors of carbapenem-resistant Enterobacteriaceae (CRE) strains in patients with COVID-19 in the ICU ward: a retrospective case-control study.

OBJECTIVE: To identify carbapenem-resistant Enterobacteriaceae (CRE) in patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; COVID-19) and to determine whether they had different risk factors for the acquisition of CRE than patients without COVID-19. METHODS: This retrospective single-centre, case-control study enrolled patients with and without COVID-19. The demographic, clinical, infection, colonization and mortality data were compared between the two groups. RESULTS: A total of 38 patients with COVID-19 and 26 patients without COVID-19 were enrolled. The majority of isolates detected in COVID-19 patients were Klebsiella spp. Leukopenia at admission (odds ratio [OR] 4.70; 95% confidence interval [CI] 1.37, 16.10), invasive mechanical ventilation (OR 5.74; 95% CI 1.07, 30.63), carbapenem treatment (OR 5.09; 95% CI 1.21, 21.27) and corticosteroid treatment (OR 7.06; 95% CI 1.53, 32.39) were independent risk factors for CRE acquisition in COVID-19 patients. Intensive care unit (ICU) mortality was significantly higher in COVID-19 patients compared with patients without COVID-19 (OR 20.62; 95% CI 5.50, 77.23). Length of ICU stay increased the risk of death in patients with COVID-19 (subdistribution hazard ratio 3.81; 95% CI 1.33, 10.92). CONCLUSION: CRE strains were more common in patients with COVID-19 and they had different risks for CRE compared with patients without COVID-19.

Impact of an antimicrobial stewardship program in a COVID-19 reference hospital according to the AWaRe classification.

This was a prospective observational study performed between January and October 2021. Antimicrobial consumption was classified according to AWaRe and expressed as daily defined doses (DDD/1000 patient-days). Watch group antibiotic consumption demonstrated a strong correlation with carbapenem resistance among both clinical and total isolates, but Acinetobacter baumannii resistance did not correlate with antimicrobial consumption. Efforts to reduce antimicrobial consumption are needed; however, prevention and control guidelines are also a cornerstone to better results.

Management of antibacterial therapy of infectious and inflammatory diseases of the urinary tract in children and regional peculiarities during the COVID-19 pandemic.

Urinary tract infections (UTIs) remain an urgent issue in clinical pediatrics. Empirical selection of antibacterial therapy becomes more complicated, and antibacterial drug indication is not always clinically substantiated. This study aimed to compare the antibacterial susceptibility pattern of the main group of urinary tract infectious agents from 2009-2016 with intermediate results from 2020-2021, during the COVID-19 pandemic, among children in the Chernivtsi region. Urine samples were collected from 3089 children (0-17 years old) treated at the health care institutions in the Chernivtsi region (2009-2016). The clinical-laboratory examination of 177 children (0-17 years old) was carried out from 2020 to 2021. The children received specialized medical care at the Department of Nephrology. Preliminary data of regional monitoring (2020-2021) are not considerably different from the previous regional susceptibility of antibiotics: to penicillin (p<0.01), ІІ-ІІІ generation cephalosporin (p<0.01); an increased resistance to levofloxacin (χ2=4,338; p<0.01), tetracycline - χ2=7,277; p<0.01; doxycycline - χ2=5,309; p<0.01) and imipenem - χ2=5,594; p<0.01). The data obtained did not explain an increased resistance to fluoroquinolones completely (ofloxacin, pefloxacin, ciprofloxacin), except for levofloxacin (χ2=4,338; p<0.01). A reliable difference of susceptibility of tetracycline group was registered (tetracycline - χ2=7,277; p<0.01; doxycycline - χ2=5,309; p<0.01). Furthermore, there was a regional increase in some UTI-pathogen strains resistant to carbapenems (imipenem - χ2=5,594; p<0.01). The use of antibiotics from the group of penicillins and II-III generation cephalosporins as the starting antibacterial therapy for STIs during the COVID-19 pandemic should be justified. A regional increase (2020-2021) of some uropathogenic strains resistant to carbapenems administered to treat severe bacterial infections requires their exclusively designated purpose in everyday pediatric practical work.

Colonization with extended-spectrum cephalosporin-resistant Enterobacterales (ESCrE) and carbapenem-resistant Enterobacterales (CRE) in healthcare and community settings in Botswana: an antibiotic resistance in communities and hospitals (ARCH) study.

OBJECTIVES: Although extended-spectrum cephalosporin-resistant Enterobacterales (ESCrE) and carbapenem-resistant Enterobacterales (CRE) are a global challenge, data on these organisms in low- and middle-income countries are limited. In this study, we sought to characterize colonization data critical for greater antibiotic resistance surveillance efforts. METHODS: This study was conducted in three hospitals and six clinics in Botswana. We conducted ongoing surveillance of adult patients in hospitals and clinics and adults and children in the community. All participants underwent rectal swab sampling to identify ESCrE and CRE. RESULTS: Enrollment occurred from January 15, 2020, to September 4, 2020, but paused from April 2, 2020, to May 21, 2020, because of a countrywide COVID-19 lockdown. Of 5088 individuals approached, 2469 (49%) participated. ESCrE colonization prevalence was 30.7% overall (43% for hospital participants, 31% for clinic participants, 24% for adult community participants, and 26% for child community participants) (P <0.001). A total of 42 (1.7%) participants were colonized with CRE. CRE colonization prevalence was 1.7% overall (6.8% for hospital participants, 0.7% for clinic participants, 0.2% for adult community participants, and 0.5% for child community participants) (P <0.001). ESCrE and CRE prevalence varied substantially across regions and was significantly higher prelockdown versus postlockdown. CONCLUSIONS: ESCrE colonization was high in all settings in Botswana. CRE prevalence in hospitals was also considerable. Colonization prevalence varied by region and clinical setting and decreased after a countrywide lockdown.

Containment of a carbapenem-resistant Acinetobacter baumannii complex outbreak in a COVID-19 intensive care unit.

BACKGROUND: A carbapenem-resistant Acinetobacter baumannii outbreak in the COVID intensive care unit of a community hospital was contained using multidrug resistant organism guidelines. The purpose of this study is to report on an outbreak investigation and containment strategy that was used, and to discuss prevention strategy. METHODS: A multidisciplinary approach contained the spread of infection. Strategies implemented included consultation with experts, screening, and reversal of personal protective equipment conservation. Ensuring infection control best practices are maintained remain important efforts to reduce the spread of multidrug resistant organisms. RESULTS: Five patients with carbapenem-resistant Acinetobacter baumannii were identified from routine clinical cultures within one week and one patient was identified from active surveillance cultures. DISCUSSION: Personal protective equipment conservation, strategies to prevent health care personnel exposure, and patient surge staffing protocols may have increased the likelihood of multidrug resistant organism transmission. Environmental and behavioral infection control regulations with effective administrative guidance, active surveillance cultures, and antimicrobial stewardship are critical to prevent future outbreaks. CONCLUSIONS: After outbreak containment strategies were implemented, no additional patients were identified with carbapenem-resistant Acinetobacter baumannii. Conventional infection prevention and control strategies were re-instituted. A multidisciplinary approach with continued focus on hand hygiene, environmental cleaning, and correct use of personal protective equipment needs to be put in place to successfully contain and prevent the spread of carbapenem resistant infections.

Oral Tebipenem Pivoxil Hydrobromide in Complicated Urinary Tract Infection.

BACKGROUND: There is a need for oral antibiotic agents that are effective against multidrug-resistant gram-negative uropathogens. Tebipenem pivoxil hydrobromide is an orally bioavailable carbapenem with activity against uropathogenic Enterobacterales, including extended-spectrum beta-lactamase-producing and fluoroquinolone-resistant strains. METHODS: In this phase 3, international, double-blind, double-dummy trial, we evaluated the efficacy and safety of orally administered tebipenem pivoxil hydrobromide as compared with intravenous ertapenem in patients with complicated urinary tract infection or acute pyelonephritis. Patients were randomly assigned, in a 1:1 ratio, to receive oral tebipenem pivoxil hydrobromide (at a dose of 600 mg every 8 hours) or intravenous ertapenem (at a dose of 1 g every 24 hours) for 7 to 10 days (or up to 14 days in patients with bacteremia). The primary efficacy end point was overall response (a composite of clinical cure and favorable microbiologic response) at a test-of-cure visit (on day 19, within a ±2-day window) in the microbiologic intention-to-treat population. The noninferiority margin was 12.5%. RESULTS: A total of 1372 hospitalized adult patients were enrolled; 868 patients (63.3%) were included in the microbiologic intention-to-treat population (50.8% of whom had complicated urinary tract infections and 49.2% of whom had pyelonephritis). An overall response was seen in 264 of 449 patients (58.8%) who received tebipenem pivoxil hydrobromide, as compared with 258 of 419 patients (61.6%) who received ertapenem (weighted difference, -3.3 percentage points; 95% confidence interval [CI], -9.7 to 3.2). Clinical cure at the test-of-cure visit was observed in 93.1% of the patients in the microbiologic intention-to-treat population who received tebipenem pivoxil hydrobromide and 93.6% of patients who received ertapenem (weighted difference, -0.6 percentage point; 95% CI, -4.0 to 2.8); the majority of patients with microbiologic response failures at the test-of-cure visit were asymptomatic patients with recurrent bacteriuria. Secondary and subgroup analyses were supportive of the primary analysis. Adverse events were observed in 25.7% of patients who received tebipenem pivoxil hydrobromide and in 25.6% of patients who received ertapenem; the most common adverse events were mild diarrhea and headache. CONCLUSIONS: Oral tebipenem pivoxil hydrobromide was noninferior to intravenous ertapenem in the treatment of complicated urinary tract infection and acute pyelonephritis and had a similar safety profile. (Funded by Spero Therapeutics and the Department of Health and Human Services; ADAPT-PO ClinicalTrials.gov number, NCT03788967.).

Treatment of valproic acid overdose with meropenem in an epileptic patient.

Valproic acid (VPA) and derivatives are effective anticonvulsants that are also used for numerous mood disorders. VPA toxicity can cause central nervous system (CNS) depression, dose related hyperammonemia, and eventually hepatotoxicity. While traditional treatment of VPA toxicity often includes l-carnitine, activated charcoal, and hemodialysis; an interaction with carbapenem class antibiotics has been well established in literature and may offer a different avenue of treatment. This case describes a 38 year-old female with a past medical history of epilepsy effectively treated with meropenem to rapidly and safely lower toxic VPA levels after an acute ingestion. A review of four VPA poisoning case reports and the interaction with carbapenem class antibiotics is also included.

Multidrug-Resistant Infections and Outcome of Critically Ill Patients with Coronavirus Disease 2019: A Single Center Experience.

Background: The aim of this study was to assess the drivers of multidrug-resistant (MDR) bacterial infection development in coronavirus disease 2019 (COVID-19) and its impact on patient outcome. Methods: Retrospective analysis on data from 32 consecutive patients with COVID-19, admitted to our intensive care unit (ICU) from March to May 2020. Outcomes considered were MDR infection and ICU mortality. Results: Fifty percent of patients developed an MDR infection during ICU stay after a median time of 8 [4-11] days. Most common MDR pathogens were carbapenem-resistant Klebsiella pneumoniae and Acinetobacter baumannii, causing bloodstream infections and pneumonia. MDR infections were linked to a higher length of ICU stay (p = 0.002), steroid therapy (p = 0.011), and associated with a lower ICU mortality (odds ratio: 0.439, 95% confidence interval: 0.251-0.763; p < 0.001). Low-dose aspirin intake was associated with both MDR infection (p = 0.043) and survival (p = 0.015). Among MDR patients, mortality was related with piperacillin-tazobactam use (p = 0.035) and an earlier onset of MDR infection (p = 0.042). Conclusions: MDR infections were a common complication in critically ill COVID-19 patients at our center. MDR risk was higher among those dwelling longer in the ICU and receiving steroids. However, MDR infections were not associated with a worse outcome.