Carbapenem-Resistant and ESBL-Producing Enterobacterales Emerging in Central Texas.

Purpose: Carbapenem-resistant Enterobacterales (CRE) are subject to intense global monitoring in an attempt to maintain awareness of prevalent and emerging resistance mechanisms and to inform treatment and infection prevention strategies. CRE and extended-spectrum beta-lactamase (ESBL)-producing Enterobacterales are not usually examined collectively in regards to their shared pool of resistance determinants. Here, we genetically and phenotypically assess clinical isolates of CRE and extended-spectrum beta-lactamase (ESBL)-producing Enterobacterales in the growing region of Central Texas, where CRE are emergent and occurrence of non-carbapenemase-producing-CRE (non-CP-CRE) infections is increasing. Methods: CRE (n=16) and ESBL-producing Enterobacterales (n=116) isolates were acquired from a regional hospital in Central Texas between December 2018 and January 2020. Isolates were assessed genetically and phenotypically using antibiotic susceptibility testing, targeted PCR, and whole genome sequencing. Results: CRE infections are increasing in incidence in Central Texas, and Klebsiella pneumoniae is causing the majority of these infections. Moreover, K. pneumoniae sequence type (ST) 307 is commonly found among both non-CP-CRE and EBSL-producing strains. Isolates carry similar plasmids harboring the gene for the ESBL CTX-M-15 and belong to the global lineage, rather than the Texas lineage, of ST307. Antibiotic resistance profiles, sequence data, and clinical records suggest that porin mutations may promote the transition of ST307 isolates from ESBL-producing to non-CP-CRE. In addition to antibiotic resistance mechanisms, several CRE isolates harbor active colicinogenic plasmids, which might influence the competitiveness of these bacteria during patient colonization. Conclusion: K. pneumoniae of the global ST307 lineage is circulating in Central Texas and is responsible for both non-CP CRE and ESBL-producing Enterobacterales infections. Enhanced surveillance is needed to understand the possible routes for the emergence of non-CP-CRE from EBSL-producing strains.

Oral ß-lactams vs fluoroquinolones and trimethoprim/sulfamethoxazole for step-down therapy for Escherichia coli, Proteus mirabilis, and Klebsiella pneumoniae bacteremia.

PURPOSE: To compare rates of treatment failure for patients with bloodstream infections (BSIs) due to Escherichia coli, Klebsiella pneumoniae, or Proteus mirabilis who received oral step-down antibiotic therapy with either a fluoroquinolone (FQ) or trimethoprim/sulfamethoxazole (SXT) to rates for those who received an oral ß-lactam (BL). METHODS: This retrospective, multicenter, cohort study included 397 unique adult hospitalized patients with a BSI due to E. coli, K. pneumoniae, or P. mirabilis at 6 hospitals in central Texas between July 11, 2016, and July 11, 2018. The primary outcome was a composite of treatment failure comprising 30-day readmission due to recurrence, 30-day all-cause mortality, and change in oral antibiotic. Secondary outcomes included 90-day development of Clostridioides difficile infection, 90-day colonization with a multidrug-resistant organism, 90-day all-cause readmission, hospital length of stay, and the individual components of the primary outcome. RESULTS: Of the 397 patients included, 200 received oral step-down therapy with a BL while 197 received an FQ or SXT. Most patients had an infection due to E. coli (82.8%) and a urinary source of infection (85%). Median total duration of therapy was 14 days in both groups. No difference in treatment failure was identified between the groups treated with a BL and FQ/SXT (7% vs 5.8%, P = 0.561). Median hospital length of stay was the only secondary endpoint in which there was an observed difference (6 vs 5 days, P = 0.04). CONCLUSION: We observed no difference in treatment failure rates for patients receiving an oral BL compared to an oral FQ or SXT for step-down therapy of BSIs due to E. coli, K. pneumoniae, and P. mirabilis.

Cefepime Versus Piperacillin-Tazobactam for the Treatment of Intra-Abdominal Infections Secondary to Potential AmpC Beta-Lactamase-Producing Organisms.

Background: Recent studies have established cefepime as an effective treatment option for AmpC beta-lactamase (AmpC) Enterobacterales; however, the efficacy of beta-lactam/beta-lactamase inhibitors is unclear. Objective: The objective of this study was to determine if piperacillintazobactamis an appropriate alternative to cefepime for the treatment of intra-abdominal infections (IAIs) secondary to AmpC-producing organisms. Methods: This multicenter, retrospective cohort study was conducted in hospitalized adults with an IAI caused by an AmpC-producing organism and received either cefepime or piperacillin-tazobactam for definitive treatment after a source control procedure. The primary outcome was a composite of surgical site infections, recurrent IAIs, or in-hospital mortality. Secondary outcomes included the individual components of the composite outcome, hospital length of stay (LOS), microbiologic failure, study antibiotic duration, time to clinical resolution, and incidence of Clostridioides difficile infection (CDI). Results: This study included 119 patients. There was no difference in the primary outcome between the cefepime and piperacillin-tazobactam groups (35% vs 27%, P = 0.14). Microbiological failure was the only secondary outcome with an observed difference between groups (17% vs 0%, P = 0.01): hospital LOS (15 vs 13 days, P = 0.09), days of therapy (7 vs 7 days, P = 0.87), time to clinical resolution (7 vs 4 days, P = 0.30), and CDI (1% vs 2%, P = 0.58) were all similar.

A Comparison of Outcomes With and Without Infectious Diseases Consultation for Enterococcal Bacteraemia in a Multicenter Healthcare System.

INTRODUCTION: It is unknown whether infectious diseases consultation improves outcomes for enterococcal bacteraemia in a multicentre healthcare system. METHODS: This retrospective multicentre observational cohort study included 250 adult patients with enterococcal bacteraemia between July 2016 and December 2020. The primary endpoint was a composite of clinical failure, including persistent bacteraemia, persistent fever, and in-hospital mortality. Secondary endpoints included adherence to a treatment bundle (appropriate empiric and definitive antibiotics, appropriate planned treatment duration, obtaining repeat blood cultures and an echocardiogram). RESULTS: Clinical failure occurred in 35 of 155 patients (22.6%) with an infectious diseases consultation and 16 of 95 patients (16.8%) without an infectious diseases consultation (P = 0.274). Multivariate analysis identified vasopressors as the only independent predictor of the primary outcome. Infectious diseases consultation resulted in higher adherence to a treatment bundle, including echocardiogram (75.5% vs. 34.7%; P < 0.0001), repeat blood cultures (85.2% vs. 68.4%; P = 0.002), appropriate definitive antibiotics (70.5% vs. 91.6%; P < 0.0001) and appropriate planned durations of therapy (81.1% vs. 94.2%; P = 0.001). More patients in the consult group were treated with ampicillin (47.1% vs. 22.1%; P < 0.0001) and fewer were treated with vancomycin (17.4% vs. 24.2%; P = 0.068). CONCLUSION: Despite finding no difference in clinical failure between groups, this study highlights important benefits of infectious diseases consultation in enterococcal bacteraemia.

Supratherapeutic Tacrolimus Concentrations With Nirmatrelvir/Ritonavir in Solid Organ Transplant Recipients Requiring Hospitalization: A Case Series Using Rifampin for Reversal.

Nirmatrelvir/ritonavir was recently granted emergency use authorization for mild to moderate coronavirus disease 2019. Drug-drug interactions between ritonavir and tacrolimus are underappreciated by nontransplant providers. We describe 2 solid organ transplant recipients prescribed nirmatrelvir/ritonavir for outpatient use who developed tacrolimus toxicity requiring hospitalization and were managed with rifampin for toxicity reversal.

Automated Susceptibility Testing With Vitek 2 Compared to MicroScan Reduces Vancomycin Alternative Therapy For Methicillin-Resistant Staphylococcus Aureus Bacteremia.

OBJECTIVES: Variability in minimum inhibitory concentration (MIC) with automated susceptibility testing instruments may influence methicillin-resistant Staphylococcus aureus (MRSA) treatment. The purpose of this study was to evaluate the difference in vancomycin MIC values and the impact on vancomycin alternative therapy for MRSA bacteremia using the MicroScan and VITEK 2 automated systems. METHODS: This was a retrospective multicenter cohort study of adult patients with MRSA bacteremia. Patients were stratified by susceptibility testing with MicroScan (May 2013-December 2016) or VITEK 2 (June 2017-February 2020). The primary outcome was vancomycin alternative therapy use. Secondary endpoints included MRSA MIC, 30-day mortality, 30- and 90-day readmission, and hospital length of stay (LOS). RESULTS: A total of 193 patients were included for analysis: 89 in the MicroScan group and 104 in the VITEK 2 group. Vancomycin alternative therapy use was higher in the MicroScan group than the VITEK 2 group (56.2% vs 20.2%; p <0.001). Median MIC value was 2 mg/L and 1 mg/L for MicroScan and VITEK 2, respectively (p <0.001). Median hospital LOS was shorter in the VITEK 2 period (16 vs 12 days; p = 0.02). Thirty-day mortality (10.1% vs 7.7%; p = 0.555) and 90-day readmission (34.8% vs 29.8%; p = 0.457) did not significantly differ between MicroScan and VITEK 2 groups. CONCLUSIONS: VITEK 2 use was associated with lower reported vancomycin MICs and less use of vancomycin alternative therapy.

Intravenous to oral antibiotics versus intravenous antibiotics: a step-up or a step-down for extended spectrum ß-lactamase (ESBL)-producing urinary tract infections without concomitant bacteraemia?

The Infectious Diseases Society of America (IDSA) recommends numerous antibiotics for the treatment of urinary tract infections (UTIs) caused by extended-spectrum ß-lactamase (ESBL)-producing bacteria. The purpose of this study was to evaluate clinical outcomes of oral step-down antibiotics compared with continued intravenous therapy in UTIs without bacteraemia. This multicentre, retrospective, cohort study was conducted in hospitalised patients with ESBL-producing UTIs between July 2016 and March 2020. The primary outcome was a composite all-cause clinical failure, defined as 30-day re-admission, 30-day hospital mortality or a change in oral antibiotics during hospitalisation. Secondary outcomes included individual primary outcome components, re-admission due to a recurrent UTI, change in antibiotic during hospitalisation, hospital length of stay (LOS), antibiotic costs and adverse events. The study included 153 patients. The primary outcome occurred in 28% of both groups (27/95 vs. 16/58; P = 0.91). The primary outcome components were similar: re-admission (26% vs. 26%; P = 0.95); hospital mortality (2% vs. 2%; P = 1.0); and change in antibiotics (0% vs. 2%; P = 0.38). Mean hospital LOS and direct antibiotic costs were 8 ± 6 days vs. 5 ± 2 days (P < 0.01) and US$278 ± 244 vs. US$180 ± 104 (P < 0.01), respectively. Adverse events were similar, except diarrhoea (15% vs. 2%; P = 0.01). There was no difference in clinical failure, re-admission rate, re-admission due to a recurrent UTI, mortality rate or antibiotic change between groups. The switch group was associated with reduced hospital LOS and inpatient antibiotic costs.

Cryptococcus neoformans blood stream infection in severe COVID-19 pneumonia.

Severe coronavirus disease (COVID-19) associated pneumonia leads to acute respiratory distress syndrome and emerging data suggest fungal coinfections also contribute to mortality in this patient population. Aspergillus ventilator associated pneumonia is increasingly recognized. We describe a case of likely reactivation of community acquired Cryptococcus neoformans in a patient with severe COVID-19.

Rethinking Carbapenems: A Pharmacokinetic Approach for Antimicrobial Selection in Infected Necrotizing Pancreatitis.

OBJECTIVE: To provide an overview of pathophysiological changes to the pancreas during infected necrotizing pancreatitis (INP), optimal drug properties needed to penetrate the pancreas, human and animal studies supporting the use of antimicrobials, and carbapenem-sparing strategies in INP. DATA SOURCES: A literature analysis of PubMed/MEDLINE was performed (from 1960 to September 2020) using the following key terms: infected necrotizing pancreatitis, necrotizing acute pancreatitis, and infected pancreatitis antimicrobial concentration. Individual antimicrobials were investigated with these search terms. STUDY SELECTION AND DATA EXTRACTION: All relevant studies describing the management of INP, and human and animal pharmacokinetic (PK) data supporting antimicrobial use in the pancreas were reviewed for possible inclusion regardless of sample size or study design. DATA SYNTHESIS: Piperacillin/tazobactam and cefepime achieve adequate pancreatic tissue concentrations in INP studies. A majority of the literature supporting carbapenem use in INP involves imipenem, and meropenem Monte Carlo simulations suggest that standard dosing regimens of meropenem may not achieve PK targets to eradicate Pseudomonas aeruginosa. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: Carbapenems are often utilized for INP treatment based on guideline recommendations. This review discusses PK data, the history of carbapenem use in INP, and the pathophysiology of pancreatitis to suggest carbapenem-sparing strategies and provides stewardship tactics such as when to start antimicrobials, which empirical antimicrobial to use, and when to discontinue antimicrobials in the INP setting. CONCLUSIONS: Noncarbapenem antipseudomonals, such as piperacillin/tazobactam and cefepime, are appropriate carbapenem-sparing options in INP, based on PK data, spectrum of activity, and risk of collateral damage.

Impact of the implementation of a rapid meningitis/encephalitis multiplex polymerase chain reaction panel on IV acyclovir duration: multicenter, retrospective cohort of adult and pediatric patients.

The standard for diagnosing meningoencephalitis includes cerebrospinal fluid (CSF) culture and viral polymerase chain reaction (PCR). Approval of the FilmArray® BioFire® Meningitis/Encephalitis (ME) panel has reduced time to detection of several pathogens and improved diagnostic sensitivity. The objective of this study was to determine the impact on intravenous (IV) acyclovir duration of the ME panel compared to previously utilized CSF studies within a large health system with a central laboratory. A multicenter quasi-experimental cohort study of adult and pediatric patients was conducted (n = 208). The primary endpoint was duration of IV acyclovir, which was decreased (41.6 v. 30.8 hours; P < 0.01) with the ME panel. Secondary outcomes including test-turnaround time (TAT) and the impact of utilizing a central laboratory were explored. Subgroup analyses demonstrated that number of daily couriers from hospital to the central laboratory (0 versus 7 versus 3 versus 2 couriers) and hospital distance from the central laboratory (0 versus 1-10 versus 11-20 versus 21-30 miles) significantly impacted TAT (P < 0.01). While duration of IV acyclovir for the entire healthcare system was reduced, the duration at individual sites was not impacted by number of couriers or distance from the central laboratory.

Clinical Utility of Methicillin-Resistant Staphylococcus aureus Nasal Screening for Antimicrobial Stewardship: A Review of Current Literature.

Significant clinical and financial consequences are associated with both inadequate and unnecessary exposure to broad-spectrum antibiotics. As such, antimicrobial stewardship programs seek objective, reliable, and cost-effective tests to identify patients at highest or lowest risk for drug-resistant organisms to guide empirical antimicrobial selection. Use of methicillin-resistant Staphylococcus aureus (MRSA) nasal screening to rule out MRSA in lower respiratory tract infections has led to significant reductions in duration of vancomycin therapy. The clinical utility of MRSA nasal screening in other types of infection remains less clear. This review describes the performance of MRSA nasal screening in predicting MRSA infection, highlights practical considerations for use of MRSA nasal screening, and provides guidance for incorporating MRSA nasal screening into clinical practice. With a high negative predictive value when the prevalence of MRSA is low, MRSA nasal screening is a valuable antimicrobial stewardship tool with potential applications beyond lower respiratory tract infections. In appropriately selected patients, negative MRSA nasal screening can prevent initiation or guide discontinuation of anti-MRSA therapy. Antimicrobial stewardship programs should develop institutional guidelines to promote proper use of MRSA nasal screening. Pharmacists are well positioned to assist with education, interpretation, and application of MRSA nasal screening results.

Population pharmacokinetics of cefepime in febrile neutropenia: implications for dose-dependent susceptibility and contemporary dosing regimens.

Alterations in cefepime pharmacokinetic (PK) exposure and decreased bacterial susceptibility increase the risk of treatment failure. The impact of susceptible-dose-dependent (SDD) minimum inhibitory concentrations (MICs), i.e. 4-8 µg/mL, on target attainment rates for cefepime in febrile neutropenia (FN) is unclear. We sought to identify optimal cefepime regimens against SDD cefepime MICs in FN using a modelling and simulation approach. Creatinine clearance (CLCr) and body surface area (BSA) covariate-adjusted models of clearance were evaluated. Monte Carlo simulations representing 10 000 patients were completed to assess various dosing strategies (i.e. 3-8 g/day infused over 0.5-24 h, replaced every 6-24 h) and predict probabilities of target attainment (PTAs) for unbound cefepime. Nine patients received cefepime 2 g every 8 h (q8h) (0.5-h infusion). A two-compartment PK model with BSA- and CLCr-adjusted clearance was fit to the data. Mean population values for total clearance (6.3 ± 1.1 L/h), intercompartmental clearance (6.9 ± 2.8 L/h), and central (14.8 ± 3.8 L) and peripheral (10.9 ± 4.6 L) distribution volumes were all estimated with <50% CV. Simulated dosing regimens of 3-4 g/day administered as continuous infusions and doses of 2 g administered q6h (0-5 h infusion) to q8h (4-h infusion) achieved ≥90% PTA at MICs up to 8 µg/mL. Simulated regimens of 1 g q8h (4-h infusion) or 1 g q6h (0.5-h infusion) achieved ≥90% PTA only against MICs up to 4 µg/mL. High-dose prolonged infusion or more frequent cefepime regimens may be necessary to treat FN organisms with SDD MICs.

Pharmacokinetics of Cefepime in Patients with Cancer and Febrile Neutropenia in the Setting of Hematologic Malignancies or Hematopoeitic Cell Transplantation.

STUDY OBJECTIVE: To evaluate the steady-state pharmacokinetic parameters of standard cefepime dosing regimens in a hematologic malignancy and hematopoietic cell transplant patient population with febrile neutropenia. DESIGN: Open-label, single-center, prospective pharmacokinetic study. SETTING: National Cancer Institute-designated cancer center. PATIENTS: Nine adults with hematologic malignancies or hematopoietic cell transplants who had febrile neutropenia and were admitted to a hematology-oncology service between January and July 2014. INTERVENTION: Patients received empirical cefepime 2 g every 8 hours, administered as a 30-minute intravenous infusion, for febrile neutropenia. MEASUREMENTS AND MAIN RESULTS: Steady-state cefepime serum concentrations were measured after at least 2 days of continuous therapy. Venous blood samples were intensively sampled between 0 and 8 hours after the start of the 30-minute infusion at steady state. Seven of the nine patients had a hematologic malignancy diagnosis of acute leukemia, lymphoma, or myeloma, and two patients had a germ cell tumor diagnosis. Noncompartmental analysis revealed mean ± SD parameters as follows at steady state: area under the plasma concentration-time curve from 0-8 hours 222.9 ± 72.9 mg hour/L, maximum concentration 120.9 ± 21.8 mg/L, clearance 9.7 ± 3.7 L/hour, apparent volume of distribution 19.2 ± 4.65 L, and elimination half-life 1.4 ± 0.3 hours. A one-compartment pharmacokinetic model identified a mean ± SD volume of distribution of 20.9 ± 1.3 L and an elimination rate constant of 0.39 ± 0.03 hour(-1) . The mean estimated percentage of time that drug concentration remains above the pathogen minimum inhibitory concentration (fT>MIC) in serum was 55%, 77%, and 99% at MICs of 16, 8, and 4 mg/L, respectively. CONCLUSION: Patients with hematologic malignancies or hematopoietic cell transplants who had febrile neutropenia demonstrated homogeneous calculated cefepime volumes and clearances. The population parameters presented in this study may aid in the calculation of patient-specific fT>MIC for similar patients.

Nearly Fatal Case of Whipple's Disease in a Patient Mistakenly on Anti-TNF Therapy.

Whipple's disease is a rare cause of chronic diarrhea and abdominal pain that may be confused with inflammatory bowel disease. We report a Whipple's case misdiagnosed as Crohn's disease in which treatment with anti-tumor necrosis factor (anti-TNF) therapy led to nearly fatal progression. Lymph node tissue obtained during laparotomy for suspected bowel necrosis stained dramatically with periodic acid-Schiff (PAS), and electron microscopy showed a bacterium consistent with Trophyrema whipplei. The patient made a remarkable recovery complicated only by cholestatic hepatitis, which was likely a treatment-associated inflammatory response. This case serves as a reminder that all granulomatous infections should be considered prior to initiation of anti-TNF therapies.