Implementation of indication-based antibiotic order sentences improves antibiotic use in emergency departments.

INTRODUCTION: Prior data have suggested that suboptimal antibiotic prescribing in the emergency department (ED) is common for uncomplicated lower respiratory tract infections (LRTI), urinary tract infections (UTI), and acute bacterial skin and skin structure infections (ABSSSI). The objective of this study was to measure the effect of indication-based antibiotic order sentences (AOS) on optimal antibiotic prescribing in the ED. METHODS: This was an IRB-approved quasi-experiment of adults prescribed antibiotics in EDs for uncomplicated LRTI, UTI, or ABSSSI from January to June 2019 (pre-implementation) and September to December 2021 (post-implementation). AOS implementation occurred in July 2021. AOS are lean process, electronic discharge prescriptions retrievable by name or indication within the discharge order field. The primary outcome was optimal prescribing, defined as correct antibiotic selection, dose, and duration per local and national guidelines. Descriptive and bivariate statistics were performed; multivariable logistic regression was used to determine variables associated with optimal prescribing. RESULTS: A total of 294 patients were included: 147 pre-group and 147 post-group. Overall optimal prescribing improved from 12 (8%) to 34 (23%) (P < 0.001). Individual components of optimal prescribing were optimal selection at 90 (61%) vs 117 (80%) (P < 0.001), optimal dose at 99 (67%) vs 115 (78%) (P = 0.036), and optimal duration at 38 (26%) vs 50 (34%) (P = 0.13) for pre- and post-group, respectively. AOS was independently associated with optimal prescribing after multivariable logistic regression analysis (adjOR, 3.6; 95%CI,1.7-7.2). A post-hoc analysis showed low uptake of AOS by ED prescribers. CONCLUSIONS: AOS are an efficient and promising strategy to enhance antimicrobial stewardship in the ED.

Effect of a multifaceted antibiotic stewardship intervention to improve antibiotic prescribing for suspected urinary tract infections in frail older adults (ImpresU): pragmatic cluster randomised controlled trial in four European countries.

OBJECTIVE: To evaluate whether antibiotic prescribing for suspected urinary tract infections in frail older adults can be reduced through a multifaceted antibiotic stewardship intervention. DESIGN: Pragmatic, parallel, cluster randomised controlled trial, with a five month baseline period and a seven month follow-up period. SETTING: 38 clusters consisting of one or more general practices (n=43) and older adult care organisations (n=43) in Poland, the Netherlands, Norway, and Sweden, from September 2019 to June 2021. PARTICIPANTS: 1041 frail older adults aged 70 or older (Poland 325, the Netherlands 233, Norway 276, Sweden 207), contributing 411 person years to the follow-up period. INTERVENTION: Healthcare professionals received a multifaceted antibiotic stewardship intervention consisting of a decision tool for appropriate antibiotic use, supported by a toolbox with educational materials. A participatory-action-research approach was used for implementation, with sessions for education, evaluation, and local tailoring of the intervention. The control group provided care as usual. MAIN OUTCOME MEASURES: The primary outcome was the number of antibiotic prescriptions for suspected urinary tract infections per person year. Secondary outcomes included the incidence of complications, all cause hospital referrals, all cause hospital admissions, all cause mortality within 21 days after suspected urinary tract infections, and all cause mortality. RESULTS: The numbers of antibiotic prescriptions for suspected urinary tract infections in the follow-up period were 54 prescriptions in 202 person years (0.27 per person year) in the intervention group and 121 prescriptions in 209 person years (0.58 per person year) in the usual care group. Participants in the intervention group had a lower rate of receiving an antibiotic prescription for a suspected urinary tract infection compared with participants in the usual care group, with a rate ratio of 0.42 (95% confidence interval 0.26 to 0.68). No differences between intervention and control group were observed in the incidence of complications (<0.01 v 0.05 per person year), hospital referrals (<0.01 v 0.05), admissions to hospital (0.01 v 0.05), and mortality (0 v 0.01) within 21 days after suspected urinary tract infections, nor in all cause mortality (0.26 v 0.26). CONCLUSIONS: Implementation of a multifaceted antibiotic stewardship intervention safely reduced antibiotic prescribing for suspected urinary tract infections in frail older adults. TRIAL REGISTRATION: ClinicalTrials.gov NCT03970356.

Baseline Inappropriate Antibiotic Use in Primary Care Patients with Viral Respiratory Tract Infections with 2019 and 2020.

Context: Respiratory tract infection (RTI) is the leading cause of avoidable antimicrobial use in primary care. How the COVID-19 pandemic has impacted antibiotic prescribing practices across Canada is unknown. The purpose of this study was to examine rates of antibiotic prescribing for RTI in primary care during the first year of the pandemic (2020), compared to baseline in 2019. Study Design and Analysis: Cross sectional study. Dataset: Canadian Primary Care Sentinel Surveillance Network electronic medical record data from sites in British Columbia, Alberta, Manitoba, Ontario, Quebec, Nova Scotia and Newfoundland. Population Studied: Patients that met the case definition criteria for an RTI or a Urinary Tract Infection (UTI) in 2019, and in 2020. Outcome measures: We examined oral antibiotic prescribing for patients who were identified as having a primary care visit for RTI. The same analysis was repeated for urinary tract infection (UTI) as a tracer condition. The antibiotic use considered avoidable for RTI was defined by Choosing Wisely Canada. Results: A total of 1,692,876 patients with a valid birth year and sex and at least one visit to primary care in 2019 and 2020 were included. Patient visits for RTI decreased from 2.3% in 2019 to 1.6% in 2020 (p<.0001), as did patient visits for UTI (1.1% vs 0.7%, p<.0001). In 2019, 28.0% of patients visits for RTI were prescribed an antibiotic, and this proportion decreased significantly to 20.6% in 2020 (<.0001). The drop in antibiotic prescriptions for RTI was driven by a decrease in prescribing for common cold (13.6% vs. 11.3%, <.0001) and for acute bronchitis/asthma (15.2% vs. 7.3%, p<.0001). In comparison, antibiotic prescribing for visits related to UTI increased marginally between 2019 and 2020 (71.6% vs. 72.3%, p=0.007). Conclusions: A significant decrease in antibiotic prescribing for RTI across primary care was observed during the first year of the COVID-19 pandemic, likely related to the changes in epidemiology and care delivery models in primary care. CPCSSN can provide pan-Canadian surveillance of antibiotic prescribing practices in primary care that can be used for provider feedback and quality improvement.

Has the COVID-19 Pandemic Affected Community-Acquired Urinary Tract Infections in Children?

PURPOSE: To evaluate whether there were any changes in the rates of urinary tract infection (UTI) and antibiotic resistance in pediatric patients during the pandemic period. MATERIALS AND METHODS: Urine culture samples collected due to suspected UTI were searched retrospectively from our hospital database, and the patients with growth in urine culture were identified. They were divided into 2 groups as Group A (before COVID-19, March 11, 2019- March 11, 2020) and Group B (COVID-19 period, March 11, 2020- March 11, 2021). Also, COVID-19 period was divided into 3 subgroups (March 2020- June 2020: first epidemic peak, July 2020 - November 2020: normalization process, December 2020- March 2021: second epidemic peak). We adjusted the patient age as <1, 1-6 and 7-18 years. Age, gender, microorganism strain types, and their antibiotic resistance patterns were compared between the 2 groups Results: This cross-sectional study included 250 eligible patients (Group A, n=182 and Group B, n=68) with a mean age of 10.91 ± 5.58 years. The male/female ratio was higher in Group B than in Group A (p = .004). Incidence of UTIs was lower in the curfew and restriction periods due to epidemic peaks than normalization process (p = .001). The proportion of E.coli decreased from 80.2% to 61.8% during the pandemic period when compared to pre-pandemic period (p = .001). Group B had lower rates of resistance to ampicillin, fosfomycin and nitrofurantoin for E.coli than Group A (p = .001, p = .012 and p = .001, respectively). Also, Group B had higher rate of uncommon microorganisms and lower rate of resistance to nitrofurantoin for E.coli than Group A in patients aged 7-18 years (p = .003 and p = .023, respectively). CONCLUSION: Our study demonstrates that the ongoing COVID-19 pandemic process has caused alterations in community-acquired UTIs in children. More hygienic lifestyle may be considered as the main factor in this change.

Risk factors for isolation of carbapenem-resistant Enterobacterales from normally sterile sites and urine.

BACKGROUND: Invasive infections caused by carbapenem-resistant Enterobacterales (CRE) are of significant concern in health care settings. We assessed risk factors for a positive CRE culture from a sterile site (invasive infection) compared to isolation from urine in a large patient cohort in Atlanta from August 2011 to December 2015. METHODS: CRE cases required isolation, from urine or a normally-sterile site, of E. coli, Klebsiella spp., or Enterobacter spp. that were carbapenem-nonsusceptible (excluding ertapenem) and resistant to all third-generation cephalosporins tested. Risk factors were compared between patients with invasive and urinary infections using multivariable logistic regression. RESULTS: A total of 576 patients had at least 1 incident case of CRE, with 91 (16%) having an invasive infection. In multivariable analysis, the presence of a central venous catheter (OR 3.58; 95% CI: 2.06-6.23) or other indwelling device (OR 2.34; 95% CI: 1.35-4.06), and recent surgery within the last year (OR 1.81; 95% CI: 1.08-3.05) were associated with invasive infection when compared to urinary infection. DISCUSSION: Health care exposures and devices were associated with invasive infections in patients with CRE, suggesting that targeting indwelling catheters, including preventing unwarranted insertion or encouraging rapid removal, may be a potential infection control intervention. CONCLUSIONS: Future infection prevention efforts to decrease CRE cases in health care settings should focus on minimizing unnecessary devices.

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.

The Effect of the COVID-19 Pandemic on Urine Culture Results and Resistance to Antibiotics in the Emergency Department.

BACKGROUND: This study aimed to investigate the effect of the COVID-19 pandemic on urine culture results and antibiotic sensitivities in patients with suspected urinary tract infections (UTI) admitted to the emergency department (ED) and determine more accurate treatment modalities for patients. The primary endpoint of our study was to determine the change in antibiotic resistance of UTI agents in the pre-and post-COVID period. METHODS: In the study, urine samples were sent from ED to the microbiology laboratory with a preliminary diagnosis of UTI between June 1, 2019, and July 1, 2021. Urine samples with the growth of 105 cfu/mL and above in urine cultures or with the growth of 103 cfu/mL and above in urine sample cultures taken from catheters were examined. At the end of the exclusions, the results of a total of 1,090 patients were evaluated. Urine cultures and an-tibiotic susceptibility tests of the patients included in the study were examined in two periods (pre-pandemic and post-pandemic). RESULTS: A total of 1,090 aerobic urine cultures sent from the ED between June 2019 and June 2021 were finalized in the microbiology laboratory. Of the 1,090 urine cultures sent from the ED within the 24 months included in the study, 497 (45.59%) were sent eight months before the COVID-19 pandemic. Growth was detected in 33 (6.63%) cultures. In the 16 months after the pandemic, 593 (54.41%) urine cultures were sent. Growth was seen in 69 (11.6%) cultures. The positivity rate obtained from urine cultures sent after the COVID-19 pandemic was significantly higher than those sent before the COVID-19 pandemic (p = 0.005). According to cultures and antibiogram results, resistance to ampicillin, cefuroxime, cefuroxime axetil, cefoxitin, cefixime, ceftazidime, ceftriaxone, and amoxicillin-clavulanic acid decreased significantly compared with pre-COVID-19 (p < 0.05). In addition, Extended Spectrum Beta-Lactamase (ESBL) resistance decreased significantly compared with the prepandemic period (p = 0.012). CONCLUSIONS: In this study, we found that the susceptible to antibiotics increased significantly in the post-COVID-19 period compared to the pre-COVID-19 period.

Possible Trichosporon asahii urinary tract infection in a critically ill COVID-19 patient.

BACKGROUND: Trichosporon asahii, an emerging fungal pathogen, has been frequently associated with invasive infections in critically ill patients. CASE REPORT: A 74-year-old male patient diagnosed with COVID-19 was admitted to an Intensive Care Unit (ICU). During hospitalization, the patient displayed episodes of bacteremia by Staphylococcus haemolyticus and a possible urinary tract infection by T. asahii. While the bacterial infection was successfully treated using broad-spectrum antibiotics, the fungal infection in the urinary tract was unsuccessfully treated with anidulafungin and persisted until the patient died. CONCLUSIONS: With the evolving COVID-19 pandemic, invasive fungal infections have been increasingly reported, mainly after taking immunosuppressant drugs associated with long-term broad-spectrum antibiotic therapy. Although Candida and Aspergillus are still the most prevalent invasive fungi, T. asahii and other agents have emerged in critically ill patients. Therefore, a proper surveillance and diagnosing any fungal infection are paramount, particularly in COVID-19 immunocompromised populations.

The impact of the coronavirus disease 2019 pandemic on changes in antimicrobial prophylaxis and development of genito-urinary tract infections after urodynamic study: A retrospective comparative study of a single rehabilitation hospital in Japan.

AIMS: To investigate the changes in the proportion of antimicrobial prophylaxis (AP) during the urodynamic study (UDS) and the frequency of posttest genito-urinary tract infections (GUTI) before and after coronavirus disease 2019 (COVID-19) pandemic, and evaluate this associations. PATIENTS AND METHODS: Patients who underwent UDS between 2015 and 2021 were targeted, and they were allocated to pre-2020 as before the appearance of COVID-19 and post-2020 as after that, and propensity score matching was performed. The impact on AP was assessed by the administration rate, and that on the development of febrile GUTI after UDS was assessed for an equivalence by the GUTI-free rate at 7 days after testing. RESULTS: After matching, 384 cases of 192 cases each were included. The frequency of AP was 58.3% in pre-2020 and 77.1% in post-2020, an increase of about 19%, and the rate increased significantly in post-2020 (p < 0.001). However, the incidence of GUTI after UDS was 4.2% and 4.7%, respectively, with no significant difference. The ratio of GUTI-free rates was within the equivalence margin, confirming an equivalence before and after the appearance of COVID-19. CONCLUSIONS: Under the influence of COVID-19 pandemic, even though AP rate during UDS was increased by 19% from that brought by following the guideline-based administration methods, the frequency of GUTI after UDS was similar, so it is thought to be important to use AP during UDS appropriately for high-risk cases as recommended in the guidelines.

The clinical and microbiological efficacy of temocillin versus cefotaxime in adults with febrile urinary tract infection, and its effects on the intestinal microbiota: a randomised multicentre clinical trial in Sweden.

BACKGROUND: Use of third-generation cephalosporins, such as cefotaxime, is associated with an increased risk of selection for antimicrobial resistance, so alternative antibiotics need to be considered. The aim of the present study was to evaluate intestinal colonisation with third-generation cephalosporin-resistant pathogens following use of temocillin-an alternative antibiotic to cefotaxime that is potentially less prone to disturbing the intestinal microbiota-in empirical treatment of febrile urinary tract infection (UTI). METHODS: We did a randomised, multicentre, superiority, open-label phase 4 trial in patients who had been admitted to inpatient care in 12 Swedish hospitals with suspected or diagnosed febrile UTI (complicated or uncomplicated). To meet inclusion criteria, a patient was required to have at least one sign or symptom of pyelonephritis (ie, flank pain; costovertebral angle tenderness; and changes to urinary frequency or urgency or dysuria), a fever of 38·0°C or higher, and a positive urine dipstick (for nitrites, white blood cells, or both). Participants were also required to have an indication for intravenous antibiotic treatment. Participants were randomly assigned (1:1) to receive either 2 g temocillin or 1-2 g cefotaxime, by local investigators opening consecutive sealed randomisation envelopes that were generated centrally in advance. Both drugs were administered intravenously every 8 h. The trial was open label for investigators and patients, but those doing the microbiological analyses were masked to the groups. Participants were treated with antibiotics for 7-10 days (or up to 14 days if they had bacteraemia), at least 3 days of which were on the study drug; at day 4 and later, participants who were showing improvement could be given an oral antibiotic (ciprofloxacin, ceftibuten, cefixime, or co-trimoxazole). Patients not showing improvement were regarded as having treatment failures. Rectal swabs were collected at three timepoints: at baseline (before the first dose), after the last dose of study drug, and 7-10 days after treatment stopped. The composite primary outcome was colonisation with Enterobacterales with reduced susceptibility to third-generation cephalosporins, or colonisation with toxin-producing Clostridioides difficile, or both, to evaluate disturbance of the intestinal microbiota. The study is registered in the EU Clinical Trials Register (EudraCT 2015-003898-15). FINDINGS: Between May 20, 2016, and July 31, 2019, 207 patients were screened for eligibility, of whom 55 patients were excluded. 152 participants were randomly assigned to groups: 77 (51%) patients received temocillin, 75 (49%) patients received cefotaxime. The composite primary endpoint was met by 18 (26%) of 68 participants receiving temocillin versus 30 (48%) of 62 patients receiving cefotaxime (risk difference -22% [95% CI -42% to -3%]), showing superiority of temocillin versus cefotaxime (ie, less disturbance of the intestinal microbiota). 43 adverse events were reported in 40 (52%) of 77 patients in the temocillin group, versus 46 adverse events in 34 (45%) of 75 patients in the cefotaxime group. Most events were of mild to moderate severity. 21 (27%) patients in the temocillin and 17 (23%) patients in the cefotaxime group had an adverse event that was considered to be associated with the study drug. INTERPRETATION: Temocillin was found to be less selective than cefotaxime of Enterobacterales with reduced susceptibility to third-generation cephalosporins, and it could therefore be a favourable alternative in the empirical treatment of febrile UTI. Use of this antibiotic could reduce hospital transmission and health-care-associated infections by these pathogens. FUNDING: Public Health Agency of Sweden.

Sulopenem: An Intravenous and Oral Penem for the Treatment of Urinary Tract Infections Due to Multidrug-Resistant Bacteria.

Sulopenem (formerly known as CP-70,429, and CP-65,207 when a component of a racemic mixture with its R isomer) is an intravenous and oral penem that possesses in vitro activity against fluoroquinolone-resistant, extended spectrum ß-lactamases (ESBL)-producing, multidrug-resistant (MDR) Enterobacterales. Sulopenem is being developed to treat patients with uncomplicated and complicated urinary tract infections (UTIs) as well as intra-abdominal infections. This review will focus mainly on its use in UTIs. The chemical structure of sulopenem shares properties of penicillins, cephalosporins, and carbapenems. Sulopenem is available as an oral prodrug formulation, sulopenem etzadroxil, which is hydrolyzed by intestinal esterases, resulting in active sulopenem. In early studies, the S isomer of CP-65,207, later developed as sulopenem, demonstrated greater absorption, higher drug concentrations in the urine, and increased stability against the renal enzyme dehydropeptidase-1 compared with the R isomer, which set the stage for its further development as a UTI antimicrobial. Sulopenem is active against both Gram-negative and Gram-positive microorganisms. Sulopenem's ß-lactam ring alkylates the serine residues of penicillin-binding protein (PBP), which inhibits peptidoglycan cross-linking. Due to its ionization and low molecular weight, sulopenem passes through outer membrane proteins to reach PBPs of Gram-negative bacteria. While sulopenem activity is unaffected by many ß-lactamases, resistance arises from alterations in PBPs (e.g., methicillin-resistant Staphylococcus aureus [MRSA]), expression of carbapenemases (e.g., carbapenemase-producing Enterobacterales and in Stenotrophomonas maltophilia), reduction in the expression of outer membrane proteins (e.g., some Klebsiella spp.), and the presence of efflux pumps (e.g., MexAB-OprM in Pseudomonas aeruginosa), or a combination of these mechanisms. In vitro studies have reported that sulopenem demonstrates greater activity than meropenem and ertapenem against Enterococcus faecalis, Listeria monocytogenes, methicillin-susceptible S. aureus (MSSA), and Staphylococcus epidermidis, as well as similar activity to carbapenems against Streptococcus agalactiae, Streptococcus pneumoniae, and Streptococcus pyogenes. With some exceptions, sulopenem activity against Gram-negative aerobes was less than ertapenem and meropenem but greater than imipenem. Sulopenem activity against Escherichia coli carrying ESBL, CTX-M, or Amp-C enzymes, or demonstrating MDR phenotypes, as well as against ESBL-producing Klebsiella pneumoniae, was nearly identical to ertapenem and meropenem and greater than imipenem. Sulopenem exhibited identical or slightly greater activity than imipenem against many Gram-positive and Gram-negative anaerobes, including Bacteroides fragilis. The pharmacokinetics of intravenous sulopenem appear similar to carbapenems such as imipenem-cilastatin, meropenem, and doripenem. In healthy subjects, reported volumes of distribution (Vd) ranged from 15.8 to 27.6 L, total drug clearances (CLT) of 18.9-24.9 L/h, protein binding of approximately 10%, and elimination half-lives (t½) of 0.88-1.03 h. The estimated renal clearance (CLR) of sulopenem is 8.0-10.6 L/h, with 35.5% ± 6.7% of a 1000 mg dose recovered unchanged in the urine. An ester prodrug, sulopenem etzadroxil, has been developed for oral administration. Initial investigations reported a variable oral bioavailability of 20-34% under fasted conditions, however subsequent work showed that bioavailability is significantly improved by administering sulopenem with food to increase its oral absorption or with probenecid to reduce its renal tubular secretion. Food consumption increases the area under the curve (AUC) of oral sulopenem (500 mg twice daily) by 23.6% when administered alone and 62% when administered with 500 mg of probenecid. Like carbapenems, sulopenem demonstrates bactericidal activity that is associated with the percentage of time that free concentrations exceed the MIC (%f T > MIC). In animal models, bacteriostasis was associated with %f T > MICs ranging from 8.6 to 17%, whereas 2-log10 kill was seen at values ranging from 12 to 28%. No pharmacodynamic targets have been documented for suppression of resistance. Sulopenem concentrations in urine are variable, ranging from 21.8 to 420.0 mg/L (median 84.4 mg/L) in fasted subjects and 28.8 to 609.0 mg/L (median 87.3 mg/L) in those who were fed. Sulopenem has been compared with carbapenems and cephalosporins in guinea pig and murine systemic and lung infection animal models. Studied pathogens included Acinetobacter calcoaceticus, B. fragilis, Citrobacter freundii, Enterobacter cloacae, E. coli, K. pneumoniae, Proteus vulgaris, and Serratia marcescens. These studies reported that overall, sulopenem was non-inferior to carbapenems but appeared to be superior to cephalosporins. A phase III clinical trial (SURE-1) reported that sulopenem was not non-inferior to ciprofloxacin in women infected with fluoroquinolone-susceptible pathogens, due to a higher rate of asymptomatic bacteriuria in sulopenem-treated patients at the test-of-cure visit. However, the researchers reported superiority of sulopenem etzadroxil/probenecid over ciprofloxacin for the treatment of uncomplicated UTIs in women infected with fluoroquinolone/non-susceptible pathogens, and non-inferiority in all patients with a positive urine culture. A phase III clinical trial (SURE-2) compared intravenous sulopenem followed by oral sulopenem etzadroxil/probenecid with ertapenem in the treatment of complicated UTIs. No difference in overall success was noted at the end of therapy. However, intravenous sulopenem followed by oral sulopenem etzadroxil was not non-inferior to ertapenem followed by oral stepdown therapy in overall success at test-of-cure due to a higher rate of asymptomatic bacteriuria in the sulopenem arm. After a meeting with the US FDA, Iterum stated that they are currently evaluating the optimal design for an additional phase III uncomplicated UTI study to be conducted prior to the potential resubmission of the New Drug Application (NDA). It is unclear at this time whether Iterum intends to apply for EMA or Japanese regulatory approval. The safety and tolerability of sulopenem has been reported in various phase I pharmacokinetic studies and phase III clinical trials. Sulopenem (intravenous and oral) appears to be well tolerated in healthy subjects, with and without the coadministration of probenecid, with few serious drug-related treatment-emergent adverse events (TEAEs) reported to date. Reported TEAEs affecting ≥1% of patients were (from most to least common) diarrhea, nausea, headache, vomiting and dizziness. Discontinuation rates were low and were not different than comparator agents. Sulopenem administered orally and/or intravenously represents a potentially well tolerated and effective option for treating uncomplicated and complicated UTIs, especially in patients with documented or highly suspected antimicrobial pathogens to commonly used agents (e.g. fluoroquinolone-resistant E. coli), and in patients with documented microbiological or clinical failure or patients who demonstrate intolerance/adverse effects to first-line agents. This agent will likely be used orally in the outpatient setting, and intravenously followed by oral stepdown in the hospital setting. Sulopenem also allows for oral stepdown therapy in the hospital setting from intravenous non-sulopenem therapy. More clinical data are required to fully assess the clinical efficacy and safety of sulopenem, especially in patients with complicated UTIs caused by resistant pathogens such as ESBL-producing, Amp-C, MDR E. coli. Antimicrobial stewardship programs will need to create guidelines for when this oral and intravenous penem should be used.

COVID-19 Clinical Profiles and Fatality Rates in Hospitalized Patients Reveal Case Aggravation and Selective Co-Infection by Limited Gram-Negative Bacteria.

Bacterial co-infections may aggravate COVID-19 disease, and therefore being cognizant of other pathogens is imperative. We studied the types, frequency, antibiogram, case fatality rates (CFR), and clinical profiles of co-infecting-pathogens in 301 COVID-19 patients. Co-infection was 36% (n = 109), while CFR was 31.2% compared to 9.9% in non-co-infected patients (z-value = 3.1). Four bacterial species dominated, namely, multidrug-resistant Klebsiella pneumoniae (37%, n = 48), extremely drug-resistant Acinetobacter baumannii (26%, n = 34), multidrug-resistant Eschericia. coli (18.6%, n = 24), and extremely drug-resistant Pseudomonas aeruginosa (8.5%, n = 11), in addition to other bacterial species (9.3%, n = 12). Increased co-infection of K. pneumoniae and A. baumannii was associated with increased death rates of 29% (n = 14) and 32% (n = 11), respectively. Klebsiella pneumoniae was equally frequent in respiratory and urinary tract infections (UTI), while E. coli mostly caused UTI (67%), and A. baumannii and P. aeruginosa dominated respiratory infections (38% and 45%, respectively). Co-infections correlated with advance in age: seniors ≥ 50 years (71%), young adults 21-49 years (25.6%), and children 0-20 years (3%). These findings have significant clinical implications in the successful COVID-19 therapies, particularly in geriatric management. Future studies would reveal insights into the potential selective mechanism(s) of Gram-negative bacterial co-infection in COVID-19 patients.

Culture Requests and Multi-Drug Resistance among Suspected Urinary Tract Infections in Two Tertiary Hospitals in Freetown, Sierra Leone (2017-21): A Cross-Sectional Study.

In sub-Saharan Africa, there is limited information about the use of microbiology laboratory services in patients with suspected urinary tract infections (UTIs). This cross-sectional study assessed the requests for urine culture in patients with suspected UTI in two tertiary (maternal and paediatric) hospitals-Freetown and Sierra Leone, during May 2017-May 2021-and determined antimicrobial resistance (AMR) patterns among bacterial isolates. One laboratory served the two hospitals, with its electronic database used to extract information. Overall, there were 980 patients, of whom 168 (17%) had cultures requested and performed. Of these, 75 (45%) were culture positive. During 2017-2019, there were 930 patients, of whom 156 (17%) had cultures performed. During 2020-2021, when services were disrupted by the COVID-19 pandemic, there were 50 patients, of whom 12 (24%) had cultures performed. The four commonest isolates were Escherichia coli (36), Klebsiella pneumoniae (10), Staphylococcus aureus (9), and Pseudomonas spp. (6). There were high levels of AMR, especially for trimethoprim-sulfamethoxazole (47%), nalidixic acid (44%), nitrofurantoin (32%) and cefotaxime (36%). Overall, 41 (55%) bacterial isolates showed multidrug resistance, especially E. coli (58%), Pseudomonas spp. (50%), and S. aureus (44%). These findings support the need for better utilization of clinical microbiology services to guide antibiotic stewardship and monitoring of trends in resistance patterns.

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.).

Impact of antimicrobial stewardship program on antimicrobial-resistance and prescribing in nursing homes: a systematic review and meta-analysis.

OBJECTIVES: The success of the antimicrobial stewardship program (ASP) is more often measured in antimicrobial use in the literature; however, there is limited evidence regarding antimicrobial resistance (AMR). This study aims to systematically review the impact of urinary tract infection-targeted ASP on overall AMR, antimicrobial use, and specific to fluoroquinolone (FQ) use in nursing homes (NHs). METHODS: This systematic review and meta-analysis included studies published in EMBASE, PubMed, Scopus, Medline, and Cochrane Central Register of Controlled Trials. Two reviewers independently extracted data in standard forms in "Covidence." The outcome was presented in percent change and rate ratio. Meta-analysis was done using DerSimonian and Laird random-effects model with inverse variance weighting. RESULTS: A total of 216 NHs participated in 16 included studies. Most of the ASP was educational, targeted to nurses and physicians. Four studies reported information about uropathogens resistance, 10 FQ-related, 13 antimicrobials prescribed, and 11 urine cultures. ASP had a positive impact on reducing overall and FQ-related AMR. However, fewer studies representation with varying information did not allow us to generalise. ASP performance was impressive in reducing antimicrobial prescribing (pooled rate ratio = 0.69, 95% CI 0.60-0.81, P ≤ 0.001) and urine culture rate (pooled rate ratio = 0.64, 95% CI 0.61-0.67, P ≤ 0.001) in NHs. CONCLUSION: The findings are encouraging despite the limited studies reported ASP impact on AMR. However, it takes years to see the impact of ASP on AMR. Therefore, future research should allocate a long-term follow-up and at least an outcome related to AMR to generate concrete evidence.

Aminopenicillins for treatment of ampicillin-resistant enterococcal urinary tract infections.

PURPOSE: The purpose of this review is to describe the theory behind and data supporting use of aminopenicillins in the treatment of ampicillin-resistant enterococcal urinary tract infections. SUMMARY: Aminopenicillin concentrations in the urine may be high enough to achieve bacterial eradication and clinical cure for infections affecting the lower genitourinary tract, even in the context of in vitro resistance based on established susceptibility breakpoints. A literature search was conducted to identify original research articles describing the use of aminopenicillins in the treatment of urinary tract infections caused by ampicillin-resistant Enterococcus species. Three published retrospective cohort studies were identified, all of which reported that aminopenicillins had similar rates of clinical cure as other antibiotic classes prescribed for the treatment of enterococcal urinary tract infections. CONCLUSION: Both pharmacokinetic/pharmacodynamic principles and limited retrospective clinical data support the use of aminopenicillins in the treatment of lower urinary tract infections caused by Enterococcus species, even when the isolates have a minimum inhibitory concentration that exceeds the susceptibility breakpoint.

Virtual learning collaboratives to improve urine culturing and antibiotic prescribing in long-term care: controlled before-and-after study.

BACKGROUND: Urine culturing practices are highly variable in long-term care and contribute to overprescribing of antibiotics for presumed urinary tract infections. The purpose of this study was to evaluate the use of virtual learning collaboratives to support long-term care homes in implementing a quality improvement programme focused on reducing unnecessary urine culturing and antibiotic overprescribing. METHODS: Over a 4-month period (May 2018-August 2018), 45 long-term care homes were self-selected from five regions to participate in virtual learning collaborative sessions, which provided an orientation to a quality improvement programme and guidance for implementation. A process evaluation complemented the use of a controlled before-and-after study with a propensity score matched control group (n=127) and a difference-in-difference analysis. Primary outcomes included rates of urine cultures performed and urinary antibiotic prescriptions. Secondary outcomes included rates of emergency department visits, hospital admission and mortality. An 18-month baseline period was compared with a 16-month postimplementation period with the use of administrative data sources. RESULTS: Rates of urine culturing and urinary antibiotic prescriptions per 1000 resident days decreased significantly more among long-term care homes that participated in learning collaboratives compared with matched controls (differential reductions of 19% and 13%, respectively, p<0.0001). There was no statistically significant changes to rates of emergency department visits, hospital admissions or mortality. These outcomes were observed with moderate adherence to the programme model. CONCLUSIONS: Rates of urine culturing and urinary antibiotic prescriptions declined among long-term care homes that participated in a virtual learning collaborative to support implementation of a quality improvement programme. The results of this study have refined a model to scale this programme in long-term care.

A global perspective on improving patient care in uncomplicated urinary tract infection: expert consensus and practical guidance.

OBJECTIVES: Uncomplicated urinary tract infections (uUTIs) are a common problem in female patients. Management is mainly based on empirical prescribing, but there are concerns about overtreatment and antimicrobial resistance (AMR), especially in patients with recurrent uUTIs. METHODS: A multidisciplinary panel of experts met to discuss diagnosis, treatment, prevention, guidelines, AMR, clinical trial design and the impact of COVID-19 on clinical practice. RESULTS: Symptoms remain the cornerstone of uUTI diagnosis, and urine culture is necessary only when empirical treatment fails or rapid recurrence of symptoms or AMR is suspected. Specific antimicrobials are first-line therapy (typically nitrofurantoin, fosfomycin, trimethoprim/sulfamethoxazole and pivmecillinam, dependent on availability and local resistance data). Fluoroquinolones are not first-line options for uUTIs primarily due to safety concerns but also rising resistance rates. High-quality data to support most non-antimicrobial approaches are lacking. Local AMR data specific to community-acquired uUTIs are needed, but representative information is difficult to obtain; instead, identification of risk factors for AMR can provide a basis to guide empirical antimicrobial prescribing. The COVID-19 pandemic has impacted the management of uUTIs in some countries and may have long-lasting implications for future models of care. CONCLUSION: Management of uUTIs in female patients can be improved without increasing complexity, including simplified diagnosis and empirical antimicrobial prescribing based on patient characteristics, including a review of recent antimicrobial use and past pathogen resistance profiles, drug availability and guidelines. Current data for non-antimicrobial approaches are limited. The influence of COVID-19 on telehealth could provide an opportunity to enhance patient care in the long term.

Clinical effectiveness and bacteriological eradication of three different Short-COurse antibiotic regimens and single-dose fosfomycin for uncomplicated lower Urinary Tract infections in adult women (SCOUT study): study protocol for a randomised clinical trial.

INTRODUCTION: Uncomplicated lower urinary tract infections (uLUTI) are a common problem in primary care. Current local guidelines recommend the use of a single 3 g dose of fosfomycin. However, most general practitioners (GP) prefer short-course therapies to single-dose therapy. No study has compared head-to-head short-course antimicrobial agents for uLUTIs. Therefore, the aim of this randomised clinical trial is to compare three different short-course antibiotic therapies with a single-dose of fosfomycin for these infections. METHODS AND ANALYSIS: This will be a pragmatic, multicentre, parallel group, open trial. Women aged 18 or older and with symptoms of uLUTI and a positive urine dipstick analysis will be randomised to one of the following four groups: a single dose of 3 g of fosfomycin, 2 days of 3 g of fosfomycin o.d., 3 days of pivmecillinam 400 mg three times per day (t.i.d) or 5 days of nitrofurantoin 100 mg t.i.d. A total sample of 1120 patients was calculated. The primary endpoint is clinical effectiveness at day 7, defined as cure of symptoms reported by the patients in a diary including four symptoms: dysuria, urgency, frequency and suprapubic pain, which will be scored on a 4-point severity scale (not present/mild/moderate/severe). Follow-up visits are scheduled at days 7 (phone call), 14 and 28 for assessing evolution. Urine samples will be collected in the three on-site visits and urine cultures performed. If positive, antibiograms for the three antibiotics studied will be performed. Bacterial eradication will be measured at days 14 and 28. ETHICS AND DISSEMINATION: The study was approved by the Ethical Board of IDIAP Jordi Gol (reference number: 21/173-AC) and Spanish Agency of Medicines and Medical Devices. The findings of this trial will be disseminated through research conferences and peer-review journals. TRIAL REGISTRATION NUMBER: NCT04959331; EudraCT Number: 2021-001332-26. TIME SCHEDULE: January 2022 to April 2023.