Respiratory virus coinfections during the COVID-19 pandemic: epidemiologic analysis and clinical outcomes from the Phase 2/3 molnupiravir trial (MOVe-OUT).

This exploratory post hoc analysis assessed the incidence of respiratory viral coinfections and their impact on clinical outcomes in non-hospitalized adults with mild-to-moderate coronavirus disease-2019 (COVID-19) treated with molnupiravir versus placebo for 5 days in the Phase 2/3 MOVe-OUT trial (NCT04575597), which took place in October 2020 to January 2021 (Phase 2, n = 302) and May 2021 to October 2021 (Phase 3, n = 1,433). Among 1,735 total randomized participants, 1,674 had a baseline respiratory pathogen panel (NxTAG Respiratory Pathogen Panel for the Luminex MAGPIX instrument) performed and 69 (4.1%) were coinfected with at least one additional respiratory viral pathogen. Human rhinovirus/enterovirus (39/69, 56.5%) was the most common coinfection detected at baseline. In the modified intention-to-treat population, two participants with coinfecting respiratory RNA viruses were hospitalized and received respiratory interventions through Day 29, and none died; one participant in the molnupiravir group was coinfected with human rhinovirus/enterovirus, and one participant in the placebo group was coinfected with human metapneumovirus. Hospitalization or death occurred in 6.2% and 9.0% of non-coinfected participants in the molnupiravir versus placebo group, respectively, and over 90% did not require respiratory interventions. Most coinfecting respiratory RNA viruses detected at baseline were not detected at the end of therapy in both the molnupiravir and placebo groups. In summary, participants coinfected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and another respiratory RNA virus were not more likely to be hospitalized or die, or require respiratory interventions, compared to participants who were not coinfected with another respiratory RNA virus at baseline in both groups. IMPORTANCE: Respiratory viral coinfections are known to occur with coronavirus disease-2019 (COVID-19). In a cohort of non-hospitalized adults with mild-to-moderate COVID-19 treated with molnupiravir versus placebo in the MOVe-OUT trial during October 2020 to October 2021, 4.1% of participants had a documented viral coinfection; human rhinovirus/enterovirus was the most common pathogen detected with the NxTAG Respiratory Pathogen Panel assay. Participants who had a coinfection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and another respiratory RNA virus were not more likely to have worse clinical outcomes compared to those participants without a viral coinfection, and many coinfecting respiratory RNA viruses were no longer detected at the end of the 5-day treatment period in both groups.

Ceftolozane-Tazobactam for the Treatment of Multidrug-Resistant Pseudomonas aeruginosa Infections: A Multicenter Study.

BACKGROUND: Multidrug-resistant Pseudomonas aeruginosa infections remain common in hospitals worldwide. We investigated the outcomes associated with the use of ceftolozane-tazobactam for the treatment of these infections. METHODS: Data were collected retrospectively from 20 hospitals across the United States about adults who received ceftolozane-tazobactam for the treatment of multidrug-resistant P aeruginosa infections of any source for at least 24 hours. The primary outcome was a composite of 30-day and inpatient mortality, and secondary outcomes were clinical success and microbiological cure. Multivariable regression analysis was conducted to determine factors associated with outcomes. RESULTS: Two-hundred five patients were included in the study. Severe illness and high degrees of comorbidity were common, with median Acute Physiology and Chronic Health Evaluation (APACHE) II scores of 19 (interquartile range [IQR], 11-24) and median Charlson Comorbidity Indexes of 4 (IQR, 3-6). Delayed initiation of ceftolozane-tazobactam was common with therapy started a median of 9 days after culture collection. Fifty-nine percent of patients had pneumonia. On susceptibility testing, 125 of 139 (89.9%) isolates were susceptible to ceftolozane-tazobactam. Mortality occurred in 39 patients (19%); clinical success and microbiological cure were 151 (73.7%) and 145 (70.7%), respectively. On multivariable regression analysis, starting ceftolozane-tazobactam within 4 days of culture collection was associated with survival (adjusted odds ratio [OR], 5.55; 95% confidence interval [CI], 2.14-14.40), clinical success (adjusted OR, 2.93; 95% CI, 1.40-6.10), and microbiological cure (adjusted OR, 2.59; 95% CI, 1.24-5.38). CONCLUSIONS: Ceftolozane-tazobactam appeared to be effective in the treatment of multidrug-resistant P aeruginosa infections, particularly when initiated early after the onset of infection.

Multicenter Study of Outcomes with Ceftazidime-Avibactam in Patients with Carbapenem-Resistant Enterobacteriaceae Infections.

Ceftazidime-avibactam is a novel cephalosporin-beta-lactamase inhibitor combination that is active against many carbapenem-resistant Enterobacteriaceae (CRE). We describe a retrospective chart review for 60 patients who received ceftazidime-avibactam for a CRE infection. In-hospital mortality was 32%, 53% of patients had microbiological cure, and 65% had clinical success. In this severely ill population with CRE infections, ceftazidime-avibactam was an appropriate option.

An Evaluation of Selected Indications and Appropriateness of Ampicillin/Sulbactam, an Unrestricted Antimicrobial, at a Single Center.

BACKGROUND: With antimicrobial resistance on the rise and few new agents in development, it is important to exercise prudent judgment when utilizing antimicrobials. The Antimicrobial Stewardship Program (ASP) is responsible for facilitating the appropriate use of antimicrobials at the institution. Restricted antimicrobials and select additional antimicrobials are monitored by the ASP team to determine if the indications chosen by the ordering prescribers correspond to and are appropriate for the patients' infections. The purpose of this study was to review ampicillin/sulbactam, an unrestricted antimicrobial, due to its declining effectiveness against Escherichia coli. METHODS: A retrospective chart review was conducted with adult inpatients receiving ampicillin/sulbactam. One hundred consecutive orders for ampicillin/sulbactam were reviewed. RESULTS: The greatest number of orders for ampicillin/sulbactam came from the Emergency Trauma, Medicine, and Surgery services. The indications selected by the ordering providers were: skin and soft tissue infection (33 orders), community-acquired respiratory infection (22 orders), other (14 orders), intra-abdominal infection due to susceptible organism (13 orders), urinary tract infection (nine orders), head/neck infection (five orders), infection due to human or animal bite (three orders), and diabetic foot infection (one order). CONCLUSIONS: The correct indication was selected in 78% of orders that were reviewed for correctness. Empiric ampicillin/sulbactam was appropriate in 51% of orders, with the majority of inappropriate empiric usage being intra-abdominal and urinary tract infections.

Vancomycin-resistant enterococcal bacteraemia and daptomycin: are higher doses necessary?

BACKGROUND: The MIC corresponding to daptomycin susceptibility for vancomycin-resistant enterococci (VRE) is ≤ 4 mg/L. Based on the concentration-dependent killing properties of daptomycin, there may be concern about achieving adequate concentrations when the MIC approaches the upper end of the susceptible range (3-4 mg/L). Higher doses of daptomycin may be needed to treat VRE isolates with higher MICs. METHODS: We conducted a single-centre retrospective chart review of adult cases with VRE bacteraemia who received daptomycin as initial therapy. The primary outcome was time to microbiological cure (TMC) between standard doses (≤ 6 mg/kg) and high doses (> 6 mg/kg) of daptomycin and whether TMC differed based on MICs. The secondary outcome evaluated the daptomycin MIC distribution and assessed whether recent exposure to vancomycin was associated with higher daptomycin MICs. RESULTS: Forty-six cases were included in the primary analysis and 60.9% of patients were neutropenic. The two dose groups differed in the baseline characteristics of age, body mass index, blood culture source and catheter removal. Median TMC was 2 days for both dose groups. There was no significant difference in TMC between MIC subgroups of ≤ 2 mg/L versus >2 and ≤ 4 mg/L. For the secondary analysis 227 VRE isolates were evaluated and 62% had daptomycin MICs of 3-4 mg/L. Each daptomycin MIC group had a similar incidence of prior vancomycin exposure. CONCLUSIONS: Based on this retrospective review we did not observe a difference in TMC based on daptomycin dose and MIC; however, there were various limitations to this study, and the study was not powered to detect a difference in TMC. Also, prior vancomycin exposure did not appear to influence daptomycin MICs. The frequency of daptomycin MICs of 3-4 mg/L reported in this study is higher than those reported in the literature.

Primary antifungal prophylaxis in adult hematopoietic stem cell transplant recipients: current therapeutic concepts.

In recipients of hematopoietic stem cell transplants (HSCTs), the mortality associated with invasive fungal infections (IFIs) remains high, despite the introduction of broad-spectrum antifungal agents over the past 2 decades. Preventing exposure to fungal pathogens in this population is impossible; therefore, clinicians have focused on prophylactic use of antifungal agents to prevent IFIs in high-risk HSCT recipients. It is important to target antifungal prophylaxis by type of HSCT (autologous or allogeneic), local epidemiology, and risk factors for IFIs so that patients can receive the most appropriate agent while balancing costs and the risks of toxicity, and minimizing the development of resistance. To assist clinicians in weighing the pros and cons of currently available antifungal agents when choosing a suitable prophylactic regimen, we provide a review of several key prospective randomized trials that evaluated various antifungal agents for primary prophylaxis in adult HSCT recipients. In addition, we describe the epidemiology of and risk factors for IFIs in HSCT recipients, the difficulties in diagnosing IFIs, antifungal agents used for prophylaxis, and the goals of primary prophylaxis. Fluconazole remains the gold standard for primary prophylaxis in autologous HSCT recipients. For allogeneic HSCT recipients, the agent chosen for prophylaxis must be based on the patient's risk factors for IFIs. In low-risk patients, fluconazole is an appropriate agent to use for primary prophylaxis immediately after transplantation. However, in allogeneic HSCT recipients who develop complications, such as graft failure, graft-versus-host disease, or cytomegalovirus infection, prophylaxis with a mould-active agent should be used.