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Antimicrobials are commonly prescribed and often misunderstood. With more than 50% of hospitalized patients receiving an antimicrobial agent at any point in time, judicious and optimal use of these drugs is paramount to advancing patient care. This narrative will focus on myths relevant to nuanced consultation from infectious diseases specialists, particularly surrounding specific considerations for a variety of antibiotics. [ABSTRACT FROM AUTHOR]

After receiving a monitored first-dose antimicrobial infusion at an infusion center, 6 of 93 (6%) patients enrolled in outpatient parenteral antimicrobial therapy services experienced an immediate reaction, none of which were consistent with immunoglobulin E-mediated reactions. These findings suggest it would be reasonable to forgo monitoring for most patients receiving first-dose intravenous antimicrobials outpatient. [ABSTRACT FROM AUTHOR]

Over the past 20 years, there has been a shift from vitamin K antagonists to direct oral anticoagulants (DOACs), which include the thrombin inhibitor dabigatran and the factor Xa inhibitors apixaban, edoxaban, and rivaroxaban. Although DOACs are associated with less serious bleeding than vitamin K antagonists, bleeding still occurs with DOACs, particularly in the elderly and in those with comorbidities. Reversal of the anticoagulant effects of the DOACs may be needed in patients with serious bleeding and in those requiring urgent surgery or intervention. Reversal can be effected with specific agents, such as idarucizumab for dabigatran and andexanet alfa for apixaban, edoxaban, and rivaroxaban, or with non-specific agents, such as prothrombin complex concentrates, activated prothrombin complex concentrate, and recombinant activated factor VII. This paper (i) provides an update on when and how to reverse the DOACs, (ii) describes new reversal agents under development, and (iii) provides a strategic framework for the reversal of the factor XI inhibitors currently under investigation in phase three clinical trials. [ABSTRACT FROM AUTHOR]

Background Bacterial infections such as osteomyelitis and endocarditis routinely require several weeks of treatment with intravenous (IV) antimicrobials. Outpatient parenteral antimicrobial therapy (OPAT) programs allow patients to receive IV antimicrobials in an outpatient clinic or at home. The outcomes and costs of such treatments remain uncertain. Methods We conducted a retrospective observational cohort study over a 5-year study interval (1 June 2012 to 31 March 2018) using population-based linked administrative data from British Columbia, Canada. Patients receiving OPAT following a hospitalization for bacterial infection were matched based on infection type and implied duration of IV antimicrobials to patients receiving inpatient parenteral antimicrobial therapy (IPAT). Cumulative adverse events and direct healthcare costs were estimated over a 90-day outcome interval. Results In a matched cohort of 1842 patients, adverse events occurred in 35.6% of OPAT patients and 39.0% of IPAT patients (adjusted odds ratio, 1.04 [95% confidence interval {CI},.83–1.30; P =.61). Relative to IPAT patients, OPAT patients were significantly more likely to experience hospital readmission (30.5% vs 23.0%) but significantly less likely to experience Clostridioides difficile diarrhea (1.2% vs 3.1%) or death (2.0% vs 8.8%). Estimated mean direct healthcare costs were $30 166 for OPAT patients and $50 038 for IPAT patients (cost ratio, 0.60; average cost savings with OPAT, $17 579 [95% CI, $14 131–$21 027]; P <.001). Conclusions Outpatient IV antimicrobial therapy is associated with a similar overall prevalence of adverse events and with substantial cost savings relative to patients remaining in hospital to complete IV antimicrobials. These findings should inform efforts to expand OPAT use. [ABSTRACT FROM AUTHOR]

A patient with end-stage renal disease received 2 doses of dalbavancin for methicillin-resistant Staphylococcus aureus (MRSA) arteriovenous fistula infection and presented 5 weeks later with infective endocarditis secondary to vancomycin, daptomycin, and dalbavancin nonsusceptible MRSA. Resistance was associated with walK and scrA mutations, reduced long-chain lipid content, and reduced membrane fluidity. [ABSTRACT FROM AUTHOR]

Background Limited data are available in the United States on the 12-month epidemiology, outpatient (OP) antibiotic treatment patterns, outcomes, and costs associated with complicated urinary tract infections (cUTIs) in adult patients. Methods A retrospective observational cohort study of adult patients with incident cUTIs in IBM MarketScan Databases between 2017 and 2019 was performed. Patients were categorized as OP or inpatient (IP) based on initial setting of care for index cUTI and were stratified by age (<65 years vs ≥65 years). OP antibiotic treatment patterns, outcomes, and costs associated with cUTIs among adult patients over a 12-month follow-up period were examined. Results During the study period, 95 322 patients met inclusion criteria. Most patients were OPs (84%) and age <65 years (87%). Treatment failure (receipt of new unique OP antibiotic or cUTI-related ED visit/IP admission) occurred in 23% and 34% of OPs aged <65 years and ≥65 years, respectively. Treatment failure was observed in >38% of IPs, irrespective of age. Across both cohorts and age strata, >78% received ≥2 unique OP antibiotics, >34% received ≥4 unique OP antibiotics, >16% received repeat OP antibiotics, and >33% received ≥1 intravenous (IV) OP antibiotics. The mean 12-month cUTI-related total health care costs were $4697 for OPs age <65 years, $8924 for OPs age >65 years, $15 401 for IPs age <65 years, and $17 431 for IPs age ≥65 years. Conclusions These findings highlight the substantial 12-month health care burden associated with cUTIs and underscore the need for new outpatient treatment approaches that reduce the persistent or recurrent nature of many cUTIs. [ABSTRACT FROM AUTHOR]

Vancomycin was introduced nearly 65 years ago and remains the standard antibiotic for serious methicillin-resistant Staphylococcus aureus (MRSA) infections. Staphylococcus aureus remains highly susceptibility to vancomycin (>97%). Despite this, MRSA treatment failure with vancomycin is high in complicated bacteremia. Additionally, vancomycin can cause nephrotoxicity, leading to new therapeutic drug monitoring guidance. This demonstrates how difficult it is to dose vancomycin in a way that is both efficacious and safe, especially during long courses of therapy. Often underappreciated are the cost, resources, and complexity of vancomycin care at a time when alternative antibiotics are becoming cost comparable. This perspective highlights a bigger picture of how the treatment repertoires of many other diseases have changed and advanced since vancomycin's introduction in the 1950s, yet the vancomycin MRSA treatment standard remains. While vancomycin can still have a role, 65 years may be a practical retirement age for vancomycin in highly complex endovascular infections. [ABSTRACT FROM AUTHOR]

The revised vancomycin guidelines recommend implementing AUC24-based therapeutic drug monitoring (TDM) using Bayesian methods in both adults and paediatrics. The motivation for this change was accumulating evidence showing aggressive dosing to achieve high troughs, as recommended in the first guidelines for adults and extrapolated to paediatrics, is associated with increased nephrotoxicity without improving clinical outcomes. AUC24-based TDM requires substantial resources that may need to be diverted from other valuable interventions. It can therefore be justified only after certain assumptions are shown to be true: (i) there is a clear relationship between vancomycin efficacy and/or toxicity and the proposed therapeutic range; and (ii) maintaining exposure within the target range with AUC24-based TDM improves clinical outcomes and/or decreases toxicity. In this review, we critically appraise the scientific basis for these assumptions. We find studies evaluating the relationship between vancomycin AUC24/MIC and efficacy in adults and children do not offer strong support for the recommended lower limit of the proposed therapeutic range (i.e. AUC24/MIC ≥400). Nephrotoxicity in children increases in a stepwise manner along the vancomycin exposure continuum but it is unclear if one parameter (AUC24 versus trough) is a superior predictor. Overall, evidence in children suggests good-to-excellent correlation between AUC24 and trough. Most importantly, there is no convincing evidence that the method of vancomycin TDM has a causal role in improving efficacy or reducing toxicity. These findings question the need to transition to resource-intensive AUC24-based TDM over retaining trough-based TDM with lower targets to minimize nephrotoxicity in paediatrics. [ABSTRACT FROM AUTHOR]

Vancomycin is commonly prescribed to hospitalized patients. Decades of pharmacokinetic/pharmacodynamic research culminated in recommendations to monitor the ratio of the area under the concentration-time curve (AUC) to the minimum inhibitory concentration in order to optimize vancomycin exposure and minimize toxicity in the revised 2020 guidelines. These guideline recommendations are based on limited data without high-quality evidence and limitations in strength. Despite considerable effort placed on vancomycin therapeutic drug monitoring (TDM), clinicians should recognize that the majority of vancomycin use is empiric. Most patients prescribed empiric vancomycin do not require it beyond a few days. For these patients, AUC determinations during the initial days of vancomycin exposure are futile. This added workload may detract from high-level patient care activities. Loading doses likely achieve AUC targets, so AUC monitoring after a loading dose is largely unnecessary for broad application. The excessive vancomycin TDM for decades has been propagated with limitations in evidence, and it should raise caution on contemporary vancomycin TDM recommendations. [ABSTRACT FROM AUTHOR]

Background It is unclear which vancomycin area under the curve (AUC) values are most associated with risk for acute kidney injury (AKI). Methods This retrospective cohort study was undertaken to determine if vancomycin AUC >550 is associated with a higher rate of AKI than an AUC <550. Patients treated with vancomycin for at least 4 days at the VA St. Louis Health Care System from 1/1/2016 to 9/31/2018 were included. The primary outcome was AKI (defined as an increase in serum creatinine by 0.3 mg/dL or 50% from baseline). Secondary outcomes included length of stay, readmission in 30 days, and mortality in 30 days. A bivariate analysis was used to determine other potential factors affecting AKI rate, with significant variables (P  < .2) to be included in the multivariate logistic regression analysis to determine independent risk for AKI. Results Two hundred patients were included in the analysis; 100 patients with an AUC ≥550 and 100 with an AUC <550. Only mean vancomycin dose (1722.50 mg vs 2361.25 mg; P  < .05), mean AUC (465.88 vs 696.45; P  < .05), and peak SCr (1.22 mg/dL vs 1.48 mg/dL; P  = .015) were significantly different between groups (AUC <550 vs AUC ≥550, respectively). AKI occurred in 42% (42/100) of patients with AUC ≥550 compared with 2% (2/100) of patients with AUC <550 (P  < .05). Secondary outcomes were not different between the groups. In the bivariate analysis, age ≥70, CrCl <50 mL/min, and AUC ≥550 (odds ratio, 49.5; 95% CI, 10.1–242.3; P  < .05) were found to be independently associated with risk for developing AKI. Conclusions Patients with a vancomycin AUC ≥550 were found to have a significantly higher rate of AKI compared with those with an AUC <550. [ABSTRACT FROM AUTHOR]

Objectives: Nephrotoxicity represents a major complication of vancomycin administration, leading to high rates of morbidity and treatment failure. The aim of this meta-analysis was to evaluate the association between trough levels and risk of renal impairment, by defining an exposure-toxicity relationship and assessing its accuracy in predicting the development of acute kidney injury (AKI).Methods: Medline, Scopus, CENTRAL, Clinicaltrials.gov and Google Scholar databases were systematically searched from inception. Studies examining the effects of trough levels on nephrotoxicity risk in adult patients were deemed eligible.Results: The meta-analysis was based on 60 studies, including 13 304 patients. The development of AKI was significantly linked to both higher initial [standardized mean difference (SMD): 0.82; 95% CI: 0.65-0.98] and maximum (SMD: 1.06; 95% CI: 0.82-1.29) trough levels. Dose-response analysis indicated a curvilinear relationship between trough levels and nephrotoxicity risk (χ2 = 127.1; P value < 0.0001). A cut-off of 15 mg/L detected AKI with a sensitivity of 62.6% (95% CI: 55.6-69.2) and a specificity of 65.5% (95% CI: 58.9-71.6), while applying a 20 mg/L threshold resulted in a sensitivity of 42.9% (95% CI: 34-52.2) and a specificity of 82.5% (95% CI: 73.9-88.8).Conclusions: The present findings suggest that the development of vancomycin-induced AKI is significantly associated with higher initial and maximum trough levels. An exposure-response relationship was defined, indicating that increasing trough levels correlate with a significant rise of nephrotoxicity risk. Future studies should verify the effectiveness of individualized pharmacokinetic tools that would enable the attainment of trough level targets and minimize the risk of renal toxicity. [ABSTRACT FROM AUTHOR]

Background Vancomycin optimization is challenging, requiring careful therapeutic drug monitoring (TDM) to avoid toxicity and ensure an efficacious concentration. Most prescriptions are empiric and often discontinued within 72 hours, which makes early TDM unnecessary. Although TDM using trough levels is common, the area under the concentration–time curve (AUC) is the preferred pharmacodynamic target. We studied the effect of a pharmacy-driven vancomycin collaborative practice agreement (CPA) at a children's hospital that delayed TDM up to 72 hours and targeted a 2-point 24-hour AUC of ≥400 mg × h/L. Methods We retrospectively reviewed vancomycin courses in patients aged ≥30 days who received vancomycin between April 1, 2011, and August 30, 2017. We implemented the CPA on June 1, 2014. Outcomes included CPA use, use of TDM, dosage adjustments, and development of acute kidney injury; we compared courses given while monitoring only trough levels (TO-TDM) with those given while using the CPA (AUC-TDM). We performed interrupted time series analyses to account for preintervention trends. Results We included 2379 courses in the TO-TDM period and 2155 in the AUC-TDM period. During AUC-TDM, 87% of the courses were managed by the CPA. In adjusted interrupted time series analyses, CPA implementation was associated with an initial change in level of −0.265 (95% confidence interval [CI], −0.336 to −0.189) TDM and an initial change in level of −0.332 (95% CI, −0.506 to −0.163) dosage adjustments. The 1-year risk of acute kidney injury decreased after CPA implementation (odds ratio, 0.695 [95% CI, 0.539–0.91]). Conclusion The pharmacy-driven vancomycin CPA resulted in less monitoring and fewer dose adjustments without increasing AKI. [ABSTRACT FROM AUTHOR]

The article offers information related to medical industry. Topics include that Measles virus infection cause loss of immune memory that can be reconstituted by reexposure to pathogens; and a case study of a 55-year-old resident with a 2-week history of fever and confirmation of a severe acute hepatitis and liver failure caused by Leishmaniasis.

Background Vancomycin is the most commonly administered antibiotic in hospitalized patients, but optimal exposure targets remain controversial. To clarify the therapeutic exposure range, this study evaluated the association between vancomycin exposure and outcomes in patients with methicillin-resistant Staphylococcus aureus (MRSA) bacteremia. Methods This was a prospective, multicenter (n = 14), observational study of 265 hospitalized adults with MRSA bacteremia treated with vancomycin. The primary outcome was treatment failure (TF), defined as 30-day mortality or persistent bacteremia ≥7 days. Secondary outcomes included acute kidney injury (AKI). The study was powered to compare TF between patients who achieved or did not achieve day 2 area under the curve to minimum inhibitory concentration (AUC/MIC) thresholds previously found to be associated with lower incidences of TF. The thresholds, analyzed separately as co-primary endpoints, were AUC/MIC by broth microdilution ≥650 and AUC/MIC by Etest ≥320. Results Treatment failure and AKI occurred in 18% and 26% of patients, respectively. Achievement of the prespecified day 2 AUC/MIC thresholds was not associated with less TF. Alternative day 2 AUC/MIC thresholds associated with lower TF risks were not identified. A relationship between the day 2 AUC and AKI was observed. Patients with day 2 AUC ≤515 experienced the best global outcomes (no TF and no AKI). Conclusions Higher vancomycin exposures did not confer a lower TF risk but were associated with more AKI. The findings suggest that vancomycin dosing should be guided by the AUC and day 2 AUCs should be ≤515. As few patients had day 2 AUCs <400, further study is needed to define the lower bound of the therapeutic range. [ABSTRACT FROM AUTHOR]

Background This study analyzed the relationship between vancomycin area under the concentration-time curve (AUC) and acute kidney injury (AKI) reported across recent studies. Methods A systematic review of PubMed, Medline, Scopus, and compiled references was conducted. We included randomized cohort and case-control studies that reported vancomycin AUCs and risk of AKI (from 1990 to 2018). The primary outcome was AKI, defined as an increase in serum creatinine of ≥0.5 mg/L or a 50% increase from baseline on ≥2 consecutive measurements. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. Primary analyses compared the impact of AUC cutpoint (greater than ~650 mg × hour/L) and AKI. Additional analysis compared AUC vs trough-guided monitoring on AKI incidence. Results Eight observational studies met inclusion/exclusion criteria with data for 2491 patients. Five studies reported first-24-hour AUCs (AUC0-24) and AKI, 2 studies reported 24- to 48-hour AUCs (AUC24-48) and AKI, and 2 studies reported AKI associated with AUC- vs trough-guided monitoring. AUC less than approximately 650 mg × hour/L was associated with decreased AKI for AUC0-24 (OR, 0.36 [95% CI,.23–.56]) as well as AUC24-48 (OR, 0.45 [95% CI,.27–.75]). AKI associated with the AUC monitoring strategy was significantly lower than trough-guided monitoring (OR, 0.68 [95% CI,.46–.99]). Conclusions AUCs measured in the first or second 24 hours and lower than approximately 650 mg × hour/L may result in a decreased risk of AKI. Vancomycin AUC monitoring strategy may result in less vancomycin-associated AKI. Additional investigations are warranted. [ABSTRACT FROM AUTHOR]

Objectives: In the absence of consensus, the present meta-analysis was performed to determine an optimal dosing regimen of vancomycin for neonates.Methods: A 'meta-model' with 4894 concentrations from 1631 neonates was built using NONMEM, and Monte Carlo simulations were performed to design an optimal intermittent infusion, aiming to reach a target AUC0-24 of 400 mg·h/L at steady-state in at least 80% of neonates.Results: A two-compartment model best fitted the data. Current weight, postmenstrual age (PMA) and serum creatinine were the significant covariates for CL. After model validation, simulations showed that a loading dose (25 mg/kg) and a maintenance dose (15 mg/kg q12h if <35 weeks PMA and 15 mg/kg q8h if ≥35 weeks PMA) achieved the AUC0-24 target earlier than a standard 'Blue Book' dosage regimen in >89% of the treated patients.Conclusions: The results of a population meta-analysis of vancomycin data have been used to develop a new dosing regimen for neonatal use and to assist in the design of the model-based, multinational European trial, NeoVanc. [ABSTRACT FROM AUTHOR]

A panel of experts was convened by the Infectious Diseases Society of America (IDSA) to update the 2004 clinical practice guideline on outpatient parenteral antimicrobial therapy (OPAT) [ 1 ]. This guideline is intended to provide insight for healthcare professionals who prescribe and oversee the provision of OPAT. It considers various patient features, infusion catheter issues, monitoring questions, and antimicrobial stewardship concerns. It does not offer recommendations on the treatment of specific infections. The reader is referred to disease- or organism-specific guidelines for such support. [ABSTRACT FROM AUTHOR]

The clinical outcomes and safety of dalbavancin as primary and sequential treatment of gram-positive bacteremia with infective endocarditis were evaluated retrospectively. The clinical success rate was high (92.6%), but in 24 of 27 patients dalbavancin was used only after clearance of bacteria from the bloodstream. [ABSTRACT FROM AUTHOR]

Background. To better monitor patients on outpatient parenteral antimicrobial therapy (OPAT), we need an improved understanding of risk factors for and timing of OPAT-associated adverse drug events (ADEs). Methods. We analyzed a prospective cohort of patients on OPAT discharged from 2 academic medical centers. Patients underwent chart abstraction and a telephone survey. Multivariable analyses estimated adjusted incident rate ratios (aIRR) between clinical and demographic risk factors and clinician-determined clinically significant ADEs. Descriptive data were used to present patient-reported ADEs. Results. Of 339 patients enrolled in the study, 18.0% experienced an ADE (N = 65), of which 49 were significant (14.5%, 2.24/1000 home-OPAT days). Patients with longer courses of therapy had lower rates of ADEs compared with patients treated for 0-13 days (14-27 days: aIRR, 0.44; 95% confidence interval [CI], 0.20-0.99; at least 28 days: aIRR, 0.11; 95% CI, 0.056-0.21). Risk factors for ADEs included female gender and receipt of daptomycin or vancomycin, while treatment for uncomplicated bacteremia and empiric treatment were associated with lower rates of ADEs. Conclusions. OPAT-related ADEs were common and often occurred within 2 weeks of hospital discharge. Patients on OPAT should be monitored more closely for ADEs, including clinical assessment and laboratory monitoring, especially within the first weeks after hospital discharge and particularly among women and patients who receive vancomycin. [ABSTRACT FROM AUTHOR]

Vancomycin remains a useful agent in the infection doctor's toolkit, particularly for Staphylococcus aureus and MRSA infections. Therapeutic drug monitoring (TDM) is essential to maintain efficacy and avoid toxicity. Until recently, trough-based dosing has been the recommended method but in recent years the reliability of this has been questioned. The 2020 Infectious Diseases Society of America (IDSA) vancomycin guideline update has sent a clear message that trough-based dosing is not to be relied on, instead recommending dosing via 24 h AUC/MIC. The UK, however, has yet to follow suit in this, despite the wealth of evidence showing that trough-based dosing puts patients at higher risk of nephrotoxicity. Clearly, it is time to incorporate AUC/MIC-based dosing to utilize this effective antibiotic safely. [ABSTRACT FROM AUTHOR]

Background Although outpatient parenteral antimicrobial therapy (OPAT) is generally considered safe, patients are at risk for complications and thus require close monitoring. The purpose of this study is to determine how OPAT programs are structured and how United States–based infectious diseases (ID) physicians perceive barriers to safe OPAT care. Methods We queried members of the Emerging Infections Network (EIN) between November and December 2018 about practice patterns and barriers to providing OPAT. Results A total of 672 members of the EIN (50%) responded to the survey. Seventy-five percent of respondents were actively involved in OPAT, although only 37% of respondents reported that ID consultation was mandatory for OPAT. The most common location for OPAT care was at home with home health support, followed by post–acute care facilities. Outpatient and inpatient ID physicians were identified as being responsible for monitoring laboratory results (73% and 54% of respondents, respectively), but only 36% had a formal OPAT program. The majority of respondents reported a lack of support in data analysis (80%), information technology (66%), financial assistance (65%), and administrative assistance (60%). The perceived amount of support did not differ significantly across employment models. Inability to access laboratory results in a timely manner, lack of leadership awareness of OPAT value, and failure to communicate with other providers administering OPAT were reported as the most challenging aspects of OPAT care. Conclusions ID providers were highly involved in OPAT, but only one-third of respondents had a dedicated OPAT program. Lack of financial and institutional support were perceived as significant barriers to providing safe OPAT care. [ABSTRACT FROM AUTHOR]