A novel 2-step process for the management of inpatient beta-lactam allergy labels.

BACKGROUND: Inpatient beta-lactam allergy labels may increase the unnecessary use of aztreonam and non-beta-lactam antibiotics, which can then lead to more adverse events and increased health care costs, OBJECTIVE: To assess the impact of a novel 2-step process (medication history review followed by risk stratification) on rates of beta-lactam delabeling, aztreonam use, and desensitizations on pediatric, adult, and obstetrics inpatients at a tertiary academic center. METHODS: We prospectively collected data on 700 patients who received inpatient consultation from the Beta-Lactam Allergy Evaluation Service between August 2021 and July 2022. Patients were delabeled either by medication review alone, drug challenge alone if with a low-risk history, or penicillin skin test followed by drug challenge if with a high-risk history. Generalized linear regression modeling was used to compare aztreonam days of therapy in the intervention year with the 2 prior years. Drug desensitizations were assessed by electronic chart review. RESULTS: Most of the patients (n = 656 of 700, 94%) had more than or equal to 1 beta-lactam allergy label removed, clarified, or both; 77.9% of these patients (n = 511 of 656) had 587 beta-lactam allergy labels removed. Nearly one-third (n = 149, 27.6%) had 162 allergy labels removed solely by medication history review. All 114 penicillin skin tests performed had negative results, and 98% (8 of 381) of the patients who underwent any drug challenge passed. Only 5.7% of the delabeled patients were relabeled. There was a 27% reduction in aztreonam use (P = .007). Beta-lactam desensitizations were reduced by 80%. CONCLUSION: A full-time inpatient beta-lactam allergy service using medication history review and risk stratification can safely and effectively remove inpatient beta-lactam allergy labels, reduce aztreonam use, and decrease beta-lactam desensitizations.

Antifungal Therapies for Aspergillus spp.: Present and Future.

Currently available and recommended options for the treatment of pulmonary aspergillosis include the triazoles, echinocandins, and amphotericin B products. These therapies have significant limitations. Only the azoles are available orally, but their use is often limited by toxicities, drug-drug interactions, pharmacokinetic variability, and emerging resistance. While the echinocandins are safe agents and may have a role in combination therapy, they are unproven as monotherapy. Amphotericin B preparations are toxic and require intensive monitoring. Finally, aspergillosis continues to be a disease conferring substantial morbidity and mortality, and clinical trials have not identified a therapeutic approach clearly associated with improved outcomes. As a result, there is a great need for new options in the treatment of invasive aspergillosis. Ideally, such options would be safe, have high oral bioavailability, have favorable pharmacokinetics to sequestered sites and retain activity against azole-resistant isolates. Reassuringly, there is a robust pipeline of novel therapies in development. Rezafungin (a once-weekly dosed echinocandin) and ibrexafungerp (oral agent with same mechanism of action as echinocandins) will likely be reserved for combination therapy or refractory/intolerance scenarios with no other options. Inhaled opelconazole is an attractive option for combination therapy and prophylaxis of pulmonary aspergillosis. Development of an oral form of amphotericin B that avoids nephrotoxicity and electrolyte disturbances is an exciting development. Finally, olorofim and fosmanogepix, two agents with novel mechanisms of action and oral formulations, hold significant potential to challenge the triazole antifungals place as preferred therapies. However, many questions remain regarding these novel agents, and at the time of this writing, none of these agents have been robustly studied in Phase III studies of aspergillosis, and so their promise remains investigational.

Tocilizumab for Treatment of Mechanically Ventilated Patients With COVID-19.

BACKGROUND: Severe coronavirus disease 2019 (COVID-19) can manifest in rapid decompensation and respiratory failure with elevated inflammatory markers, consistent with cytokine release syndrome for which IL-6 blockade is an approved treatment. METHODS: We assessed effectiveness and safety of IL-6 blockade with tocilizumab in a single-center cohort of patients with COVID-19 requiring mechanical ventilation. The primary endpoint was survival probability postintubation; secondary analyses included an ordinal illness severity scale integrating superinfections. Outcomes in patients who received tocilizumab compared with tocilizumab-untreated controls were evaluated using multivariable Cox regression with propensity score inverse probability of treatment weighting (IPTW). RESULTS: 154 patients were included, of whom 78 received tocilizumab and 76 did not. Median follow-up was 47 days (range, 28-67). Baseline characteristics were similar between groups, although tocilizumab-treated patients were younger (mean: 55 vs 60 years), less likely to have chronic pulmonary disease (10% vs 28%), and had lower D-dimer values at time of intubation (median: 2.4 vs 6.5 mg/dL). In IPTW-adjusted models, tocilizumab was associated with a 45% reduction in hazard of death (HR, .55; 95% CI, .33-.90) and improved status on the ordinal outcome scale [OR per 1-level increase, .58; .36-.94). Although tocilizumab was associated with an increased proportion of patients with superinfections (54% vs 26%; P < .001), there was no difference in 28-day case fatality rate among tocilizumab-treated patients with versus without superinfection (22% vs 15%; P = .42). Staphylococcus aureus accounted for ~50% of bacterial pneumonia. CONCLUSIONS: In this cohort of mechanically ventilated COVID-19 patients, tocilizumab was associated with lower mortality despite higher superinfection occurrence.

Macrolide-resistant Mycoplasma pneumoniae pneumonia in transplantation: Increasingly typical?

Mycoplasma pneumoniae is one of the most common bacterial causes of pneumonia. Macrolide-resistant M pneumoniae (MRMP) was documented in 7.5% of isolates in the United States. Resistance portends poor outcomes to macrolide therapy, yet patients respond well to fluoroquinolones or tetracyclines such as minocycline. However, MRMP may be under-appreciated because M pneumoniae generally causes relatively mild infections in non-immunosuppressed adults that may resolve without effective therapy and because microbiological confirmation and susceptibility are not routinely performed. We report two cases of pneumonia due to MRMP in kidney transplant recipients. Both patients required hospital admission, worsened on macrolide therapy, and rapidly defervesced on doxycycline or levofloxacin. In one case, M pneumoniae was only identified by multiplex respiratory pathogen panel analysis of BAL fluid. Macrolide resistance was confirmed in both cases by real-time PCR and point mutations associated with macrolide resistance were identified. M pneumoniae was isolated from both cases, and molecular genotyping revealed the same genotype. In conclusion, clinicians should be aware of the potential for macrolide resistance in M pneumoniae, and may consider non-macrolide-based therapy for confirmed or non-responding infections in patients who are immunocompromised or hospitalized.

Survival in Patients with Candida glabrata Bloodstream Infection Is Associated with Fluconazole Dose.

Robust pharmacodynamic indices that align fluconazole dose or exposure with outcomes in invasive candidiasis due to Candida glabrata remain elusive. The purpose of this retrospective multicenter study was to evaluate a cohort of 127 patients with C. glabrata fungemia treated with fluconazole, using adjusted analyses to identify risk factors for 28-day death. No significant correlations were found between fluconazole area under the curve (AUC), AUC/MIC ratio, or MIC and survival. In multivariate logistic regression analyses, however, higher average fluconazole dose (odds ratio [OR], 1.006 [95% confidence interval [CI], 1.001 to 1.010]; P = 0.008), average fluconazole dose of ≥400 mg (OR, 3.965 [95% CI, 1.509 to 10.418]; P = 0.005), and higher fluconazole dose on day 1 of therapy (OR, 1.007 [95% CI, 1.002 to 1.011]; P = 0.002) were found to be independent predictors of 28-day survival. Additionally, the presence of a central venous catheter at the time of infection was found to be a significant risk factor for death. In conclusion, we found fluconazole dose to be an independent predictor of 28-day survival for patients with C. glabrata fungemia, with doses of ≥400 mg/day being associated with 28-day survival rates approaching 90%. These data indicate the use and efficacy of fluconazole in the treatment of this serious infection. Aggressive dosing appears to be necessary when fluconazole is used for the treatment of C. glabrata fungemia, irrespective of MIC.

Are In Vitro Susceptibilities to Azole Antifungals Predictive of Clinical Outcome in the Treatment of Candidemia?

The purpose of this review is to critically analyze published data evaluating the impact of azole pharmacokinetic and pharmacodynamic parameters, MICs, and Candida species on clinical outcomes in patients with candidemia. Clinical breakpoints (CBPs) for fluconazole and voriconazole, which are used to determine susceptibility, have been defined by the Clinical and Laboratory Standards Institute (CLSI) for Candida species. Studies evaluating the relationship between treatment efficacy and in vitro susceptibility, as well as the pharmacodynamic targets, have been conducted in patients treated with fluconazole for candidemia; however, for species other than Candida albicans and Candida glabrata, and for other forms of invasive candidiasis, data remain limited and randomized trials are not available. Limited data evaluating these relationships with voriconazole are available. While pharmacodynamic targets for posaconazole and isavuconazole have been proposed based upon studies conducted in murine models, CBPs have not been established by CLSI. Fluconazole remains an important antifungal agent for the treatment of candidemia, and data supporting its use based on in vitro susceptibility are growing, particularly for C. albicans and C. glabrata Further investigation is needed to establish the roles of voriconazole, posaconazole, and isavuconazole in the treatment of candidemia and for all agents in the treatment of other forms of invasive candidiasis.

Dose Timing of Aminoglycosides in Hemodialysis Patients: A Pharmacology View.

Aminoglycosides for patients undergoing intermittent hemodialysis (IHD) have traditionally been dosed at half the normal dose administered at the end of a hemodialysis session. Several investigations have suggested that administering higher doses preceding or with the initiation of dialysis would more readily optimize pharmacodynamic parameters. However, the selection of an optimal aminoglycoside dosing strategy in patients receiving IHD is complex and requires consideration of numerous factors, precluding a singular approach. By reviewing aminoglycoside pharmacokinetics, pharmacodynamics, risks for toxicity and resistance development, and practical considerations, we derive indication- and setting- specific recommendations. We identify some areas (definitive therapy of gram-negative infections in patients receiving predictable hemodialysis sessions, for example) where dosing preceding or with the initiation of dialysis is optimal and feasible, and others (gram-positive synergy, unstable patients with poor/unpredictable vascular access) where postdialysis dosing remains preferred. Finally, given the dearth of data exploring the pharmacodynamics and clinical outcomes of IHD patients receiving aminoglycoside therapy, we identify several key questions in need of investigation.

Doripenem MICs and ompK36 porin genotypes of sequence type 258, KPC-producing Klebsiella pneumoniae may predict responses to carbapenem-colistin combination therapy among patients with bacteremia.

Treatment failures of a carbapenem-colistin regimen among patients with bacteremia due to sequence type 258 (ST258), KPC-2-producing Klebsiella pneumoniae were significantly more likely if both agents were inactive in vitro, as defined by a colistin MIC of >2 µg/ml and the presence of either a major ompK36 porin mutation (guanine and alanine insertions at amino acids 134 and 135 [ins aa 134-135 GD], IS5 promoter insertion [P = 0.007]) or a doripenem MIC of >8 µg/ml (P = 0.01). Major ompK36 mutations among KPC-K. pneumoniae strains are important determinants of carbapenem-colistin responses in vitro and in vivo.

Is Fluconazole or an Echinocandin the Agent of Choice for Candidemia.

OBJECTIVE: Candidemia is among the most common nosocomial bloodstream infections and is associated with high mortality, increased length of hospital stay, and significant economic burden. The introduction of the echinocandins in the 2000s has expanded the armamentarium against Candida spp and provides therapeutic options that are effective, safe, and tolerable. Although the Infectious Diseases Society of America favors echinocandins as treatment for candidemia in selected settings (at least as initial therapy), there remain divergent opinions about whether an echinocandin or fluconazole is the preferred agent for candidemia, and clinical practice guidelines are in flux. In this review, the currently available laboratory and clinical data are summarized and critically evaluated. DATA SOURCES: A MEDLINE search of the English language literature was performed using the search terms echinocandin, fluconazole, and candidemia. References of review articles and guidelines were also screened for inclusion. STUDY SELECTION AND DATA EXTRACTION: Studies whose primary goal was to compare echinocandins with fluconazole were evaluated as well as studies that differentiated pharmacological and pharmacokinetic properties between agents. DATA SYNTHESIS: It is clear that echinocandins and fluconazole each have roles in the management of candidemia. Specific recommendations are provided that will hopefully optimize outcomes in candidemia while incorporating stewardship concepts of cost-effectiveness and limiting the emergence of resistance. CONCLUSIONS: Despite the advantages brought by the echinocandins and fluconazole, outcomes among patients with candidemia remain suboptimal. Improved treatment of candidemia may ultimately be achieved by optimizing the use of antifungal agents rather than the development of new drugs.

Bringing the "power" to Cerner's PowerChart for antimicrobial stewardship.

The electronic medical record (EMR) has huge potential for facilitating antimicrobial stewardship efforts by directing providers to preferred antimicrobials. Cerner PowerChart currently holds the number 2 position in the EMR market. Although PowerChart has limited "out of the box" functionalities to optimize stewardship efforts, there are many potential utilities that can be developed to assist in stewardship practice. However, to harness the stewardship potential of the EMR system, significant hospital information technology resources are needed. Herein we describe the experiences of 3 large healthcare systems utilizing Cerner to facilitate prior authorization of antimicrobials, prospective audit and feedback of antimicrobials, and supplemental stewardship strategies.

Real-world experience with echinocandin MICs against Candida species in a multicenter study of hospitals that routinely perform susceptibility testing of bloodstream isolates.

Reference broth microdilution methods of Candida echinocandin susceptibility testing are limited by interlaboratory variability in caspofungin MICs. Recently revised Clinical and Laboratory Standards Institute (CLSI) breakpoint MICs for echinocandin nonsusceptibility may not be valid for commercial tests employed in hospital laboratories. Indeed, there are limited echinocandin susceptibility testing data from hospital laboratories. We conducted a multicenter retrospective study of 9 U.S., Australian, and New Zealand hospitals that routinely tested Candida bloodstream isolates for echinocandin susceptibility from 2005 to 2013. Eight hospitals used Sensititre YeastOne assays. The Candida spp. were C. albicans (n=1,067), C. glabrata (n=911), C. parapsilosis (n=476), C. tropicalis (n=185), C. krusei (n=104), and others (n=154). Resistance and intermediate rates were ≤1.4% and ≤3%, respectively, for each echinocandin against C. albicans, C. parapsilosis, and C. tropicalis. Resistance rates among C. glabrata and C. krusei isolates were ≤7.5% and ≤5.6%, respectively. Caspofungin intermediate rates among C. glabrata and C. krusei isolates were 17.8% and 46.5%, respectively, compared to ≤4.3% and ≤4.4% for other echinocandins. Using CLSI breakpoints, 18% and 19% of C. glabrata isolates were anidulafungin susceptible/caspofungin nonsusceptible and micafungin susceptible/caspofungin nonsusceptible, respectively; similar discrepancies were observed for 38% and 39% of C. krusei isolates. If only YeastOne data were considered, interhospital modal MIC variability was low (within 2 doubling dilutions for each agent). In conclusion, YeastOne assays employed in hospitals may reduce the interlaboratory variability in caspofungin MICs against Candida species that are observed between reference laboratories using CLSI broth microdilution methods. The significance of classifying isolates as caspofungin intermediate and anidulafungin/micafungin susceptible will require clarification in future studies.

Fluconazole versus an echinocandin for Candida glabrata fungaemia: a retrospective cohort study.

OBJECTIVES: We studied whether fluconazole or echinocandin treatment of Candida glabrata fungaemia results in superior outcomes. METHODS: A multicentre, retrospective study was performed with 224 adult patients who received ≥ 5 days of therapy with either fluconazole or an echinocandin as their first antifungal treatment after collection of a blood culture that grew C. glabrata. The primary outcome was day 14 complete response. RESULTS: Patients in the echinocandin group were generally more ill, both at baseline and at the time of the index culture. Day 14 complete response was obtained in 58/127 (46%) and 50/97 (52%) of the fluconazole and echinocandin patients, respectively (P=0.383). Logistic regression found intensive care unit admission to be associated with failure [OR 0.456 (0.217-0.957), P=0.038] and echinocandin therapy to be associated with day 14 complete response [OR 2.305 (1.124-4.727), P=0.023]. Twenty-eight day survival was similar between the fluconazole and echinocandin groups and logistic regression did not reveal antifungal therapy choice to be independently predictive of mortality. For patients treated with fluconazole, a dose:MIC ratio >12.5 (when compared with a ratio ≤ 12.5) was associated with a significantly higher day 14 complete response [4/20 (20%) ≤ 12.5 versus 50/102 (49%) >12.5, P=0.025]. CONCLUSIONS: Severity of illness and choice of antifungal predict response in patients with C. glabrata fungaemia. Antifungal choice, however, does not influence mortality. In addition, new CLSI C. glabrata fluconazole susceptibility breakpoints are predictive of response when fluconazole is dosed appropriately.

Review of Pharmacologic Considerations in the Use of Azole Antifungals in Lung Transplant Recipients.

Mold-active azole antifungals are commonly prescribed for the prevention of invasive fungal infections in lung transplant recipients. Each agent exhibits a unique pharmacologic profile, an understanding of which is crucial for therapy selection and optimization. This article reviews pharmacologic considerations for three frequently-used azole antifungals in lung transplant recipients: voriconazole, posaconazole, and isavuconazole. Focus is drawn to analysis of drug-interactions, adverse drug reactions, pharmacokinetic considerations, and the role of therapeutic drug monitoring with special emphasis on data from the post-lung transplant population.

Monoclonal Antibodies for Early Treatment of COVID-19 in a World of Evolving SARS-CoV-2 Mutations and Variants.

Monoclonal antibodies targeting the receptor binding domain (RBD) of severe acute respiratory syndrome coronavirus 2 spike protein are important outpatient treatment options in coronavirus disease 2019 to mitigate progression of disease and prevent hospitalization. The impact of different RBD mutations on the efficacy of the available monoclonal antibodies and processes for incorporating this impact into treatment algorithms are ill defined. Herein, we synthesize the data surrounding the impact of key RBD mutations on the efficacy of US Food and Drug Administration Emergency Use Authorized monoclonal antibodies and describe our approach at Michigan Medicine at monitoring mutation frequency in circulating virus and developing an algorithm that incorporates these data into outpatient treatment pathways.

The impact of delaying the initiation of appropriate antifungal treatment for Candida bloodstream infection.

We performed a retrospective analysis of the time to initiation of appropriate antifungal therapy for candidemia and in-hospital mortality. The definition of appropriate antifungal therapy was based on in vitro susceptibility results, and in the case of fluconazole, pharmacodynamic parameters. Of 123 patients, the mortality rate in the <24 h, 24-48 h, and >48 h groups was 50%, 28%, and 32%, respectively. Patients who never received antifungal treatment had a 61% mortality rate (difference between groups, P =0.06). Multivariate analysis found APACHE II score (AOR = 1.09, 95% CI: 1.02-1.17 for each point increase) to be the only independent predictor of mortality. The time to initiation of appropriate antifungal therapy did not correlate with in-hospital mortality.

Incorporating preauthorization into antimicrobial stewardship pharmacist workflow reduces Clostridioides difficile and gastrointestinal panel testing.

OBJECTIVE: To evaluate whether incorporating mandatory prior authorization for Clostridioides difficile testing into antimicrobial stewardship pharmacist workflow could reduce testing in patients with alternative etiologies for diarrhea. DESIGN: Single center, quasi-experimental before-and-after study. SETTING: Tertiary-care, academic medical center in Ann Arbor, Michigan. PATIENTS: Adult and pediatric patients admitted between September 11, 2019 and December 10, 2019 were included if they had an order placed for 1 of the following: (1) C. difficile enzyme immunoassay (EIA) in patients hospitalized >72 hours and received laxatives, oral contrast, or initiated tube feeds within the prior 48 hours, (2) repeat molecular multiplex gastrointestinal pathogen panel (GIPAN) testing, or (3) GIPAN testing in patients hospitalized >72 hours. INTERVENTION: A best-practice alert prompting prior authorization by the antimicrobial stewardship program (ASP) for EIA or GIPAN testing was implemented. Approval required the provider to page the ASP pharmacist and discuss rationale for testing. The provider could not proceed with the order if ASP approval was not obtained. RESULTS: An average of 2.5 requests per day were received over the 3-month intervention period. The weekly rate of EIA and GIPAN orders per 1,000 patient days decreased significantly from 6.05 ± 0.94 to 4.87 ± 0.78 (IRR, 0.72; 95% CI, 0.56-0.93; P = .010) and from 1.72 ± 0.37 to 0.89 ± 0.29 (IRR, 0.53; 95% CI, 0.37-0.77; P = .001), respectively. CONCLUSIONS: We identified an efficient, effective C. difficile and GIPAN diagnostic stewardship approval model.

Tocilizumab for treatment of mechanically ventilated patients with COVID-19.

BACKGROUND: Severe COVID-19 can manifest in rapid decompensation and respiratory failure with elevated inflammatory markers. This presentation is consistent with cytokine release syndrome in chimeric antigen receptor T cell therapy, for which IL-6 blockade is approved treatment. METHODS: We assessed effectiveness and safety of IL-6 blockade with tocilizumab in a single-center cohort of patients with COVID-19 requiring mechanical ventilation. The primary endpoint was survival probability post-intubation; secondary analyses included an ordinal illness severity scale integrating superinfections. Outcomes in patients who received tocilizumab compared to tocilizumab-untreated controls were evaluated using multivariable Cox regression with propensity score inverse probability weighting (IPTW). FINDINGS: 154 patients were included, of whom 78 received tocilizumab and 76 did not. Median follow-up was 47 days (range 28-67). Baseline characteristics were similar between groups, although tocilizumab-treated patients were younger (mean 55 vs. 60 years), less likely to have chronic pulmonary disease (10% vs. 28%), and had lower D-dimer values at time of intubation (median 2.4 vs. 6.5 mg/dL). In IPTW-adjusted models, tocilizumab was associated with a 45% reduction in hazard of death [hazard ratio 0.55 (95% CI 0.33, 0.90)] and improved status on the ordinal outcome scale [odds ratio per 1-level increase: 0.59 (0.36, 0.95)]. Though tocilizumab was associated with an increased proportion of patients with superinfections (54% vs. 26%; p<0.001), there was no difference in 28-day case fatality rate among tocilizumab-treated patients with versus without superinfection [22% vs. 15%; p=0.42]. INTERPRETATION: In this cohort of mechanically ventilated COVID-19 patients, tocilizumab was associated with a decreased likelihood of death despite higher superinfection occurrence. Randomized controlled trials are urgently needed to confirm these findings.

Evolving role of early antifungals in the adult intensive care unit.

BACKGROUND: Invasive candidiasis (IC) is associated with significant morbidity and mortality in critically ill patients. This, in conjunction with difficulties in diagnosis, underscores the need for novel treatment strategies based on the identification of significant risk factors for IC. OBJECTIVE: To review the evidence surrounding the use of early antifungals in critically ill adult patients and to present concise and specific recommendations for different early treatment strategies for IC. DATA SOURCES AND DATA EXTRACTION: Pubmed search from 1966 to July 2008 using the search terms "antifungals, critical care, prophylaxis, preemptive therapy, and empiric therapy." Examined all relevant peer-reviewed original articles, meta-analyses, guidelines, consensus statements, and review articles. CONCLUSION: The use of early antifungal therapy should be reserved for patients with a high risk (10% to 15%) of developing IC. Despite a large number of articles published on this topic, there is no single predictive rule that can adequately forecast IC in critically ill patients. Until further prospective validation of existing data is completed, clinicians should assess patients on a case-by-case basis and determine the need for early antifungal treatment strategies based on frequent evaluations of risk factors and clinical status.