Sulopenem Disk Development, Quality Control Range, and MIC to Disk Result Correlation for Enterobacterales Isolates.

Sulopenem disk masses of 2, 5, 10, and 20 µg were evaluated by susceptibility testing isolates by broth microdilution and disk diffusion. A 2-µg disk was chosen, and error-rate bounding analysis in accordance with Clinical and Laboratory Standards Institute (CLSI) guideline M23 was conducted using a proposed sulopenem susceptible/intermediate/resistant (S/I/R) interpretive criterion of ≤0.5/1/≥2 µg/mL. Among the evaluated Enterobacterales (n = 2,856), very few interpretive errors were observed (no very major errors and only one major error). An eight-laboratory quality control (QC) study was performed using the 2-µg disk, and 99.0% (470/475) of results were within a 7-mm range of 24 to 30 mm. Results were similar by disk lot and media, and no outlier sites were observed. A sulopenem 2-µg disk QC range for Escherichia coli 29522 of 24 to 30 mm was established by the CLSI. A 2-µg sulopenem disk performs accurately and reproducibly for testing of Enterobacterales.

In vitro activity of sulopenem and comparator agents against Enterobacterales and anaerobic clinical isolates collected during the SENTRY Antimicrobial Surveillance Program.

OBJECTIVES: Physicians must leverage several factors when making antibiotic therapy decisions, including route of administration and duration of therapy. Oral administration provides several potential advantages including increased accessibility, prevention of hospitalizations and earlier discharges. Sulopenem-a broad-spectrum, synthetic penem ß-lactam agent-uniquely possesses both oral and IV formulations along with noted stability among antimicrobial-resistant subsets. This study evaluated the in vitro activity of sulopenem and comparator agents against contemporary Enterobacterales and anaerobic clinical isolates predominantly from patients with bloodstream, intra-abdominal and urinary tract infections. METHODS: A contemporary collection of 1647 Enterobacterales and 559 anaerobic isolates was assembled from medical centres in Europe and the USA. Isolates were susceptibility tested using the CLSI reference methods: broth microdilution for Enterobacterales and agar dilution for anaerobes. RESULTS: Sulopenem demonstrated potent in vitro antimicrobial activity (MIC50/90, 0.03/0.25 mg/L) against Enterobacterales isolates regardless of infection type, inhibiting 99.2% of isolates at ≤1 mg/L. This activity was conserved against resistant phenotypes including ESBL-phenotype Escherichia coli (MIC50/90, 0.03/0.06 mg/L) and ESBL-phenotype Klebsiella pneumoniae (MIC50/90, 0.06/1 mg/L). Sulopenem maintained activity against ciprofloxacin-, nitrofurantoin- and trimethoprim/sulfamethoxazole-non-susceptible subsets (MIC50/90, 0.03-0.06/0.12-0.5 mg/L). Against anaerobic isolates, sulopenem (98.9% inhibited at ≤4 mg/L) and meropenem [98.4% susceptible (CLSI)] were the most active compounds tested. CONCLUSIONS: The potent in vitro activity of sulopenem against this large collection of recent Enterobacterales and anaerobic clinical isolates from multiple infection types supports its further clinical evaluation in the treatment of intra-abdominal and urinary tract infections.

Sulopenem for the Treatment of Complicated Urinary Tract Infections Including Pyelonephritis: A Phase 3, Randomized Trial.

BACKGROUND: Sulopenem is a thiopenem antibiotic being developed for the treatment of multidrug-resistant infections. The availability of both intravenous (IV) and oral formulations will facilitate earlier hospital discharge. METHODS: Hospitalized adults with pyuria, bacteriuria, and signs and symptoms of complicated urinary tract infection (cUTI) were randomized to 5 days of IV sulopenem followed by oral sulopenem etzadroxil/probenecid or 5 days of IV ertapenem followed by oral ciprofloxacin or amoxicillin-clavulanate, depending on uropathogen susceptibility. The primary end point was overall combined clinical and microbiologic response at the test-of-cure visit (day 21). RESULTS: Of 1392 treated patients, 444 and 440 treated with sulopenem and ertapenem, respectively, had a positive baseline urine culture and were eligible for the primary efficacy analyses. Extended-spectrum ß-lactamase-producing organisms were identified in 26.6% of patients and fluoroquinolone-nonsusceptible pathogens in 38.6%. For the primary end point, noninferiority of sulopenem to the comparator regimen was not demonstrated, 67.8% vs 73.9% (difference, -6.1%; 95% confidence interval, -12.0 to -.1%). The difference was driven by a lower rate of asymptomatic bacteriuria in the subgroup of ertapenem-treated patients who stepped down to ciprofloxacin. No substantial difference in overall response was observed at any other time point. Both IV and oral formulations of sulopenem were well-tolerated and compared favorably to the comparator. CONCLUSIONS: Sulopenem followed by oral sulopenem-etzadroxil/probenecid was not noninferior to ertapenem followed by oral step-down therapy for the treatment of cUTIs, driven by a lower rate of asymptomatic bacteriuria in those who received ciprofloxacin. Both formulations of sulopenem were well-tolerated. CLINICAL TRIAL REGISTRATION: NCT03357614.

Sulopenem or Ciprofloxacin for the Treatment of Uncomplicated Urinary Tract Infections in Women: A Phase 3, Randomized Trial.

BACKGROUND: There are limited treatment options for uncomplicated urinary tract infection (uUTI) caused by resistant pathogens. Sulopenem etzadroxil/probenecid (sulopenem) is an oral thiopenem antibiotic active against multidrug-resistant pathogens that cause uUTIs. METHODS: Patients with uUTI were randomized to 5 days of sulopenem or 3 days of ciprofloxacin. The primary endpoint was overall success, defined as both clinical and microbiologic response at day 12. In patients with ciprofloxacin-nonsusceptible baseline pathogens, sulopenem was compared for superiority over ciprofloxacin; in patients with ciprofloxacin-susceptible pathogens, the agents were compared for noninferiority. Using prespecified hierarchical statistical testing, the primary endpoint was tested in the combined population if either superiority or noninferiority was declared in the nonsusceptible or susceptible population, respectively. RESULTS: In the nonsusceptible population, sulopenem was superior to ciprofloxacin, 62.6% vs 36.0% (difference, 26.6%; 95% confidence interval [CI], 15.1 to 7.4; P <.001). In the susceptible population, sulopenem was not noninferior to ciprofloxacin, 66.8% vs 78.6% (difference, -11.8%; 95% CI, -18.0 to 5.6). The difference was driven by a higher rate of asymptomatic bacteriuria (ASB) post-treatment in patients on sulopenem. In the combined analysis, sulopenem was noninferior to ciprofloxacin, 65.6% vs 67.9% (difference, -2.3%; 95% CI, -7.9 to 3.3). Diarrhea occurred more frequently with sulopenem (12.4% vs 2.5%). CONCLUSIONS: Sulopenem was noninferior to ciprofloxacin in the treatment of uUTIs. Sulopenem was superior to ciprofloxacin in patients with uUTIs due to ciprofloxacin-nonsusceptible pathogens. Sulopenem was not noninferior in patients with ciprofloxacin-susceptible pathogens, driven largely by a lower rate of ASB in those who received ciprofloxacin. CLINICAL TRIAL REGISTRATION: NCT03354598.

Increased rates of extended-spectrum beta-lactamase isolates in patients hospitalized with culture-positive urinary Enterobacterales in the United States: 2011 - 2020.

Antimicrobial resistance in Enterobacterales has made empiric therapy for hospitalized patients with urinary tract infections (UTIs) more challenging. We analyzed the antibiotic susceptibility of nonduplicate Enterobacterales isolates from urine cultures tested at US hospitals in the BD Insights Research Database (2011-2020). Multivariable generalized estimating equation models were used to assess resistance trends over time. A total of 322 US hospitals provided data on 876,507 urinary Enterobacterales isolates (62.4% Escherichia coli). Enterobacterales antibiotic resistance rates were 64.6%, 29.3%, 27.6%, and 26.3% for beta-lactams, fluoroquinolones, nitrofurantoin, and trimethoprim/sulfamethoxazole, respectively, and 12.4% had an extended-spectrum beta-lactamase (ESBL) phenotype. In multivariable models, rates of ESBL isolates and isolates resistant to ≥3 drug classes increased significantly between 2011 and 2020, while other categories of resistance generally decreased. We conclude that antimicrobial resistance is common in urinary Enterobacterales isolates. Management of UTIs should be guided by urine culture data and may benefit from new therapies.

Regional Differences in Antibiotic-resistant Enterobacterales Urine Isolates in the United States: 2018-2020.

Antimicrobial resistance (AMR) can complicate effective management of urinary tract infections. We conducted a retrospective study of AMR in Enterobacterales urine isolates from ambulatory and hospitalized adult patients from 2018-2020 (BD Insights Research Database) to evaluate regional differences in isolates with an extended-spectrum beta-lactamase-producing phenotype and those not susceptible to beta-lactams, fluoroquinolone (FQ), nitrofurantoin (NFT), trimethoprim/sulfamethoxazole (TMP/SMX), or multiple antibiotic classes (≥ 2 or ≥ 3). Our analyses included 349,741 Enterobacterales urine isolates from 321 inpatient facilities and 980,354 isolates from 338 ambulatory care facilities. In multivariable analyses, the highest rate of resistance was to beta-lactams (60.8% and 55.8% for inpatient and ambulatory settings, respectively), followed by FQ (27.5%), NFT (27.0%), and TMP/SMX (25.4%) for inpatients and by TMP/SMX (22.4%), FQ (21.6%), and NFT (21.6%) for ambulatory patients. Isolates with an extended-spectrum beta-lactamase-producing phenotype (13.2% and 8.6% for inpatient and ambulatory settings, respectively) and multidrug resistance (inpatient and ambulatory rates of 23.4% and 17.7% for ≥ 2 drugs; 9.9% and 6.4% for ≥ 3 drugs) were also prevalent. Statistically significant differences by geographic region (P ≤ 0.005) were observed for AMR classes in both inpatient and ambulatory settings, but the rates remained above the thresholds recommended for empiric urinary tract infection therapy across most regions.

A multicenter analysis of trends in resistance in urinary Enterobacterales isolates from ambulatory patients in the United States: 2011-2020.

BACKGROUND: Urinary tract infections (UTIs), which are usually caused by bacteria in the Enterobacterales family, are a common reason for outpatient visits. Appropriate empiric therapy for UTIs requires an understanding of antibiotic resistance in the community. In this nationwide study, we examined trends in antibiotic resistance in urinary Enterobacterales isolates from ambulatory patients in the United States (US). METHODS: We analyzed the antimicrobial susceptibility profiles (extended-spectrum beta-lactamase [ESBL]-producing phenotype and not susceptible [NS] to beta-lactams, trimethoprim/sulfamethoxazole [TMP/SMX], fluoroquinolones [FQ], or nitrofurantoin [NFT]) of 30-day non-duplicate Enterobacterales isolates from urine cultures tested at ambulatory centers in the BD Insights Research Database (2011-2020). The outcome of interest was the percentage of resistant isolates by pathogen and year. Multi-variable generalized estimating equation models were used to assess trends in resistance over time and by additional covariates. RESULTS: A total of 338 US facilities provided data for > 2.2 million urinary Enterobacterales isolates during the 10-year study. Almost three-quarters (72.8%) of Enterobacterales isolates were Escherichia coli. Overall unadjusted resistance rates in Enterobacterales isolates were 57.5%, 23.1%, 20.6%, and 20.2% for beta-lactams, TMP/SMX, FQ, and NFT, respectively, and 6.9% had an ESBL-producing phenotype. Resistance to two or more antibiotic classes occurred in 16.4% of isolates and 5.5% were resistant to three or more classes. Among isolates with an ESBL-producing phenotype, 70.1%, 59.9%, and 33.5% were NS to FQ, TMP/SMX, and NFT, respectively. In multivariable models, ESBL-producing and NFT NS Enterobacterales isolates increased significantly (both P < 0.001), while other categories of resistance decreased. High rates (≥ 50%) of beta-lactam and NFT resistance were observed in Klebsiella isolates and in non-E. coli, non-Klebsiella Enterobacterales isolates. CONCLUSIONS: Antimicrobial resistance was common in urinary Enterobacterales isolates. Isolates with an ESBL-producing phenotype increased by about 30% between 2011 and 2020, and significant increases were also observed in NFT NS Enterobacterales isolates. Resistance rates for all four antibiotic classes were higher than thresholds recommended for use as empiric therapy. Non-E. coli Enterobacterales isolates showed high levels of resistance to commonly used empiric antibiotics, including NFT. These data may help inform empiric therapy choices for outpatients with UTIs.

Impact of Empirical Antibiotic Therapy on Outcomes of Outpatient Urinary Tract Infection Due to Nonsusceptible Enterobacterales.

Resistance to oral antibiotics commonly used to treat outpatient urinary tract infections (UTIs) is increasing, but the implications of empirical treatment of resistant pathogens are not well described. Using an electronic records database, we reviewed the outcomes of patients >18 years of age who developed an outpatient UTI and had an outpatient urine culture result showing a member of the order Enterobacterales along with prescription data for an oral antibiotic filled on the day before, day of, or day after the culture was collected. Linear probability models were used to estimate partial effects of select clinical and demographic variables on the composite outcome. In all, 4,792 patients had 5,587 oral antibiotic prescriptions. Of 5,395 evaluable episodes, 22% of patients received an antibiotic to which the pathogen was resistant in vitro, and those patients were almost twice as likely to require a second prescription (34% versus 19%) or be hospitalized (15% versus 8%) within 28 days of the initial prescription fill compared to patients who received an antibiotic to which the pathogen was susceptible. Approximately 1% of Enterobacterales isolates were resistant to all commonly available classes of oral antibiotics. A greater risk of treatment failure was seen in patients over 60 years of age, patients with diabetes mellitus, men, and those treated with an antibiotic when prior culture identified an organism resistant to that class. The increasing resistance among members of Enterobacterales responsible for outpatient UTIs is limiting the effectiveness of empirical treatment with existing antibiotics, and consequently, outpatients with UTI are more likely to require additional courses of therapy or be hospitalized. IMPORTANCE Resistance rates for bacteria that cause urinary tract infections (UTIs) have increased dramatically. Regional rates of resistance to commonly prescribed antibiotics now exceed 20%, which is the threshold at which the Infectious Diseases Society of America recommends therapy be guided by culture. Our goals were to describe outcomes for outpatients with UTIs caused by bacteria resistant to empirically chosen antibiotics and to create a simple stratification schema for clinicians to identify UTI patients at increased risk of treatment failure due to antibiotic mismatch. These data are relevant to clinicians, given how common uncomplicated UTIs are, and highlight the need for clinicians to understand local resistance rates and the importance of culture-guided treatment, especially in vulnerable patients. These findings also showed that 1% of bacteria were resistant to all major classes of oral antibiotics, underscoring the need for new antibiotics to treat patients with UTIs due to resistant bacteria.

Diagnosing Ring-Enhancing Lesions in the Brain of a Patient With AIDS Without Brain Biopsy: A Case of Central Nervous System Histoplasmoma.

We report a case of a Puerto Rican male with advanced AIDS who presented with multiple falls and pancytopenia. Magnetic resonance imaging (MRI) of the brain, as initial workup, revealed 2 ring-enhancing brain lesions. Initial cerebrospinal fluid analysis revealed minimal cells, mildly elevated protein, and no organism seen on gram stain. Due to prohibitive thrombocytopenia, brain biopsy was deferred. He had neither clinical nor radiographic improvement despite empiric therapy for both toxoplasmosis and bacterial abscesses. Indicated by pancytopenia, bone marrow (BM) aspiration was performed. Culture of BM aspirate grew Histoplasma capsulatum. Urine histoplasma antigen was markedly elevated. He was treated with liposomal amphotericin B (LamB) for progressive disseminated histoplasmosis with probable central nervous system involvement. Cerebrospinal fluid histoplasma antigen obtained after 2 months of LamB was detected. After prolonged course of LamB, he took itraconazole. Brain MRI at 7-month follow-up revealed significant improvement from baseline study.

Antibiotic Prophylaxis in Blepharoplasty: Review of the Current Literature.

The purpose of this study was to provide an evidence-based overview of antibiotic prophylaxis in blepharoplasty. We performed a literature search that evaluated the risk of infection associated with blepharoplasty, as well as the risks and benefits of antibiotic prophylaxis. The overall infection rate associated with eyelid surgery is extremely low. However, the use of antibiotic prophylaxis has increased over the past 25 years in esthetic facial procedures. There is no standard of care for or against antibiotic prophylaxis, and routine practices vary widely. This leads to the question of whether reducing the risk of surgical-site infection to near zero outweighs the real danger of antibiotic-related complications, including the escalating emergence of antibiotic-resistant bacteria. No direct consensus can be drawn from the current literature; thus, at this time, there is no current standard of care for oral and maxillofacial surgeons to adhere to in terms of when and if antibiotic prophylaxis is needed when performing blepharoplasty.

An Overview of Infections Associated With Soft Tissue Facial Fillers: Identification, Prevention, and Treatment.

PURPOSE: The purpose of this study was to provide an overview of infections associated with facial soft tissue fillers. MATERIALS AND METHODS: A literature review was performed which evaluated infections associated with facial soft tissue fillers. RESULTS: Infection rates with soft tissue fillers are low and are estimated at 0.04 to 0.2%. Most of these infections arise when skin contaminants infiltrate the injection site at the time of injection. These infections can occur early, up to several days after treatment, or delayed, occurring weeks to years after treatment. Reactions vary based on the filler absorbability and duration. Early recognition and treatment are important factors in managing our cosmetic surgery patients. CONCLUSION: Although facial fillers are safe and predictable, infections can still occur. Oral and maxillofacial surgeons need to be able to prevent, recognize, and properly manage infections related to these popular injections.

Adherence to standard of care in the diagnosis and treatment of suspected bacterial meningitis.

Acute bacterial meningitis (ABM) is a rare but deadly neurological emergency. Accordingly, Infectious Diseases Society of America (IDSA) guidelines summarize current evidence into a straightforward algorithm for its management. The goal of this study is to evaluate the overall compliance with these guidelines in patients with suspected ABM. A retrospective cross-sectional study was conducted of adult patients who underwent lumbar puncture for suspected ABM to ascertain local adherence patterns to IDSA guidelines for bacterial meningitis. Primary outcomes included appropriate utilization of neuroimaging, blood cultures, antibiotics, corticosteroids, and lumbar puncture. In all, 160 patients were included in the study. Overall IDSA compliance was only 0.6%. Neuroimaging and blood cultures were appropriately utilized in 54.3% and 47.5% of patients, respectively. Steroids and antibiotics were appropriately administered in only 7.5% and 5.6% of patients, respectively. Adherence to IDSA guidelines is poor. Antibiotic choice is often incorrect, corticosteroids are rarely administered, and there is an overutilization of neuroimaging.

A depiction of imported malaria in Connecticut.

In 2010, there were roughly 219 million cases of malaria reported worldwide resulting in an estimated 660,600 deaths [1]. In contrast, the total number of cases according to the Centers for Disease Control and Prevention (CDC) in the United States (USA) was only 1691 [2]. Of those, 1688 were cases of imported malaria [2]. This is the highest number of cases reported in U.S. since 1980 [2]. Here, we describe a case of imported malaria and conduct a retrospective case series at four Connecticut (CT) hospitals in order to describe the demographics of imported malaria and to identify potential barriers to timely diagnosis and treatment.

Nomenclature and definitions for emergency department human immunodeficiency virus (HIV) testing: report from the 2007 conference of the National Emergency Department HIV Testing Consortium.

Early diagnosis of persons infected with human immunodeficiency virus (HIV) through diagnostic testing and screening is a critical priority for individual and public health. Emergency departments (EDs) have an important role in this effort. As EDs gain experience in HIV testing, it is increasingly apparent that implementing testing is conceptually and operationally complex. A wide variety of HIV testing practice and research models have emerged, each reflecting adaptations to site-specific factors and the needs of local populations. The diversity and complexity inherent in nascent ED HIV testing practice and research are associated with the risk that findings will not be described according to a common lexicon. This article presents a comprehensive set of terms and definitions that can be used to describe ED-based HIV testing programs, developed by consensus opinion from the inaugural meeting of the National ED HIV Testing Consortium. These definitions are designed to facilitate discussion, increase comparability of future reports, and potentially accelerate wider implementation of ED HIV testing.

Complement C7 deficiency presenting as recurrent aseptic meningitis.

BACKGROUND: Complement deficiency states are rare inherited disorders that may predispose affected individuals to angioedema, collagen vascular disease, or infection due to encapsulated organisms, especially Neisseria meningitidis. OBJECTIVES: To report the case of a 36-year-old man of Irish descent with recurrent culture-negative neutrophilic meningitis, to offer potential reasons for the inability to recover a causative pathogen, and to review the genetics and prevalence of complement deficiency states, the methods of screening for such deficiencies, the features of meningococcal infection as they relate to such deficiencies, and management strategies for clinicians caring for patients with such deficiencies. METHODS: The patient presented in 1988 and again in 2002 with culture-negative neutrophilic meningitis. His second episode was characterized by a rash suggestive of meningococcal infection, prompting immunologic evaluation. RESULTS: Immunologic evaluation revealed an undetectable CH50 level. Levels of C1, C2, and C5 through C9 were normal except for C7, which was undetectable. Further testing revealed that the patient's sister was also C7 deficient. CONCLUSIONS: Complement component deficiencies are relatively rare; individuals with collagen vascular disease and systemic neisserial infection should be screened using either the CH50 or the APH-50 assay. Key to the management of a late-complement component-deficient host is counseling, education about meningococcal infection, and discussions about the potential benefits of chemoprophylaxis and immunoprophylaxis. The ability to detect the bacterial cause of meningitis in such patients is organism dependent and may be influenced by factors such as cerebrospinal fluid bacterial concentration and previous antibiotic drug exposure.

Severe acute respiratory syndrome.

Severe acute respiratory syndrome (SARS) is a new respiratory illness due to a novel coronavirus called SARS-CoV. Cases of SARS were first identified from Guangdong Province in southern China in November 2002. Over the next several months, international travel allowed for the rapid spread of >8,000 cases over three continents. The economic and psychological impact of this mysterious illness was profound. In order to better educate the public about this emerging infectious disease, we describe the characteristics of SARS-CoV and review the epidemiology, clinical presentation, laboratory, radiographic and histopathological features, diagnosis, treatment, prevention and infection control issues pertaining to SARS. While a significant amount of information about this disease has been gained in a brief period of time, details regarding the origin of SARS-CoV, its stability in the environment and in human body fluids, and whether it has become established in humans remain unknown.

Current pharmacotherapy of pneumococcal meningitis.

Streptococcus pneumoniae is the leading cause of bacterial meningitis for people of all age groups after infancy. Prior to the emergence of penicillin-resistant pneumococci as the cause of meningitis, penicillin was the traditional therapy for this life-threatening infection. Treatment guidelines for both suspected and confirmed cases of pneumococcal meningitis (PM) have had to evolve in response to the phenomenon of increasing antibiotic resistance. In addition, research efforts have attempted to clarify the role of dexamethasone and the importance of prompt antibiotic therapy in the management of patients with PM. This article provides a review of general therapeutic principles, current treatment guidelines and alternative therapeutic choices for patients with PM.