A damaging inflammatory response is implicated in the pathogenesis of severe coronavirus disease 2019 (COVID-19), but mechanisms contributing to this response are unclear. In two prospective cohorts, early non-neutralizing, afucosylated IgG antibodies specific to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were associated with progression from mild to more severe COVID-19. In contrast to the antibody structures that were associated with disease progression, antibodies that were elicited by mRNA SARS-CoV-2 vaccines were instead highly fucosylated and enriched in sialylation, both modifications that reduce the inflammatory potential of IgG. To study the biology afucosylated IgG immune complexes, we developed an in vivo model that revealed that human IgG-Fc gamma receptor (FcγR) interactions could regulate inflammation in the lung. Afucosylated IgG immune complexes isolated from COVID-19 patients induced inflammatory cytokine production and robust infiltration of the lung by immune cells. By contrast, vaccine-elicited IgG did not promote an inflammatory lung response. Together, these results show that IgG-FcγR interactions are able to regulate inflammation in the lung and may define distinct lung activities associated with the IgG that are associated with severe COVID-19 and protection against infection with SARS-CoV-2.

Physiologic alterations seen in obesity commonly impact the pharmacokinetics (PK) and pharmacodynamics (PD) of antibiotics and may result in suboptimal dosing in this expanding but understudied population. Much of the published clinical and PK evidence to date consists of small patient populations and are retrospective with, not infrequently, heterogeneous results that in some cases are contradictory. In the last 10 years, additional antimicrobial PK/PD and clinical data encompassing prolonged infusion strategies and examination of critically ill populations have emerged to inform antimicrobial dosing in obesity. In this narrative review, we critically review literature on dosing, PK, and possible dosing strategies in obese adults. We searched PubMed, Scopus, and the Cochrane Library using Medical Subject Headings including anti-infectives, specific antimicrobial names, obese, pharmacokinetics, and others. We reviewed articles, cross-referenced select cited references, and when applicable, referenced drug databases and package inserts to develop dosing recommendations. We provide an overall critical review of the available data regarding PK and dosing issues including dosing recommendations in both critically ill and noncritically ill patients with significant obesity. We developed dosing recommendations for 34 antimicrobials based on 121 articles of the 2336 identified by the search strategy. Although 11 of these do not appear to require dose adjustment, obesity-specific dosing guidance is provided for the remaining 23 antimicrobials. Additional studies are needed to better understand and resolve discrepant published results regarding the PK of antibiotics to establish optimal dosing strategies in obese adults. Alternative dosing strategies, such as extended infusions, should be considered for time-dependent antibiotics (e.g., β-lactams) in obese patients to achieve PD targets reliably. Therapeutic drug monitoring across the spectrum of antimicrobials is of increasing importance in this and other populations to ensure optimized dosing.

to stimulate the degradation of p53 and leads to an increase in the levels and activity of p53. Seven murine tissues express an alternatively spliced mdm2 mRNA that can encode p76 MDM2 but not p90 MDM2 , as well as the normally spliced mdm2 mRNA that encodes both MDM2 proteins. All seven tissues express both MDM2 proteins. p90 MDM2 is much more abundant than p76 MDM2 in the testis, brain, heart, and kidney. However, in those tissues known to undergo p53-mediated apoptosis in response to ␥-irradiation, the thymus, spleen, and intestine, the levels of the MDM2 proteins are roughly equivalent. Our results indicate that the ratio of the two MDM2 proteins may regulate the response of tissues to DNA damage.

STUDY OBJECTIVE The optimal pharmacodynamic parameter for the prediction of efficacy of vancomycin is the area under the concentration-time curve (AUC), and current published data indicate that dosing based on vancomycin trough concentrations is an inaccurate substitute. In this study, our objective was to compare the achievement of therapeutic target attainment after switching from a trough-based to an AUC-based dosing strategy as a part of our institution's vancomycin-per-pharmacy protocol. DESIGN Prospective observational quality assurance study. SETTING Academic medical center. PATIENTS A total of 296 hospitalized adults who received vancomycin and monitoring under our institution's vancomycin-per-pharmacy protocol were included in the analysis. The preimplementation retrospective comparison group consisted of 179 patients in whom vancomycin was initiated using a trough-based dosing strategy between November 22, 2017, and January 22, 2018. The postimplementation group included 117 patients in whom vancomycin was initiated using an AUC-based dosing strategy using two-point sampling between June 19, 2018, and July 19, 2018, after hospital-wide implementation of this protocol on June 19, 2018. MEASUREMENTS AND MAIN RESULTS AUC values were calculated from two vancomycin concentrations (peak and trough). The primary outcome was achievement of therapeutic AUC values (400-800 mgÁhr/L) in the postimplementation group or therapeutic trough level values (10-20 mg/L) in the preimplementation group. Only 98 (55%) of 179 initial trough values were therapeutic in the preimplementation group (trough-only dosing method) versus 86 (73.5%) of 117 initial AUC values in the postimplementation group (AUC-based dosing method) (p=0.0014). A lower proportion of supratherapeutic AUC values was observed in the postimplementation group compared with supratherapeutic trough concentrations in the preimplementation group (1.7% vs 18%, p<0.0001). Overall, 62% of patients with initially therapeutic AUC values had subsequent trough value increases of 25% or greater, occurring at a median of 6 days of vancomycin therapy. Nephrotoxicity occurred in 11% of patients in the preimplementation versus 9.4% in the postimplementation group (p=0.70). CONCLUSION Compared with a trough concentration-based dosing strategy, AUC-based dosing using two-point sampling improved therapeutic target attainment. Implementation is feasible at any hospital that performs vancomycin peak concentration testing and is a workable alternative to using Bayesian software for estimating AUC. This approach should also be directly compared with AUC-based dosing using Bayesian software.

This cross-sectional survey study investigates COVID-19 vaccine intentions among racially and ethnically diverse samples of health workers and the general population.

Infections caused by methicillin-resistant Staphylococcus aureus (MRSA) result in significant morbidity and mortality for patients in both community and health care settings. This is primarily due to the difficulty in treating MRSA, which is often resistant to multiple classes of antibiotics. Understanding the mechanisms of antimicrobial resistance (AMR) in MRSA provides insight into the optimal use of antimicrobial agents in clinical practice and also underpins critical aspects of antimicrobial stewardship programs. In this review we delineate the mechanisms, prevalence, and clinical importance of resistance to antibiotics licensed in the past 20 years that target MRSA, as well as new drugs in the pipeline which are likely to be licensed soon. Current gaps in scientific knowledge about MRSA resistance mechanisms are discussed, and topics in the epidemiology of AMR in S. aureus that require further investigation are highlighted.

Rationale for review International travel facilitates the spread of drug-resistant infections, including sexually transmitted infections (STIs). In 2016, the World Health Organization highlighted the global burden of ‘curable’ STIs, estimating 376 million new infections of gonorrhoea, chlamydia, syphilis and trichomoniasis annually, with considerable geographic variation in both the burden of disease and prevalence of resistance. Travelers’ risk of contracting and transmitting drug-resistant STIs depends in part on their geographic exposure. In this review, we describe the epidemiology of antimicrobial resistance (AMR) and the management of these four common STIs and Mycoplasma genitalium, an increasingly recognized cause of non-gonococcal urethritis. Key findings Multi-drug and extensively drug resistant gonorrhoea strains have been associated with international spread, particularly in travelers returning from Southeast Asia. Chlamydia is the most common bacterial STI worldwide. Although in vitro resistance has been reported, surveillance data suggest that clinically significant resistance to macrolides and tetracyclines is rare. Macrolide resistance in syphilis is now endemic in much of the world but there is no documented penicillin resistance, which remains first-line therapy. Trichomoniasis is the most common non-viral STI worldwide. Although clinical failure after treatment occurs, resistance to metronidazole is thought to be uncommon. Mycoplasma genitalium exhibits intrinsic resistance to many antibiotics, and the prevalence of resistance to both first- and second-line regimens (macrolides and fluoroquinolones) is increasing worldwide, with limited alternative therapeutic options. Recommendations International travelers are at risk for acquiring resistant STIs with limited therapeutic options. Improved diagnostics are urgently needed to improve AMR surveillance and the management of infected patients. As no vaccinations are currently available for these STIs, and pre-exposure prophylaxis is an area of active study with limited data, condom use is critical for prevention. Travel medicine providers should incorporate STI risk reduction counselling, with an emphasis on condom use, into the routine pre-travel consultation.

Background Using published data, we sought to compare outcomes in patients transitioned to either oral fluoroquinolones (FQs) or trimethoprim-sulfamethoxazole (TMP-SMX) vs ß-lactams (BLs) after an initial intravenous (IV) course for gram-negative rod (GNR) bacteremia. Methods We conducted a systematic review of PubMed and EMBASE and published IDWeek abstracts. We included studies that reported all-cause mortality and/or infection recurrence in patients transitioned to oral FQ/TMP-SMX and BLs. Results Eight retrospective studies met inclusion criteria with data for 2289 patients, of whom 65% were transitioned to oral FQs, 7.7% to TMP-SMX, and 27.2% to BLs. Follow-up periods ranged from 21 to 90 days. All-cause mortality was not significantly different between patients transitioned to either FQ/TMP-SMX or BLs (odds ratio [OR], 1.13; 95% confidence interval [CI], 0.69–1.87). Overall recurrence of infection, either bacteremia or the primary site, occurred more frequently in patients transitioned to oral BLs vs FQs (OR, 2.05; 95% CI, 1.17–3.61). Analysis limited to recurrent bacteremia was similarly suggestive, although limited by small numbers (OR, 2.15; 95% CI, 0.93–4.99). However, based on known pharmacokinetics/pharmacodynamics, prescribed ß-lactam dosing regimens were frequently suboptimal. Conclusions In the step-down IV to oral treatment of GNR bacteremia, we found insufficient data regarding outcomes after oral TMP-SMX; however, selection of an FQ over commonly utilized ß-lactam regimens may reduce chances of infection recurrence. Although this may be a class effect, it may simply be the result of inadequate dosing of ß-lactams. Additional investigations are warranted to determine outcomes with TMP-SMX and optimized oral ß-lactam dosing regimens.