Overconsumption of Antibiotics

We applaud Thomas Van Boeckel and colleagues1 for their large analysis of antibiotic consumption in 71 countries. A 36% increase in use of antibiotics worldwide, 76% of which was in Brazil, Russia, India, China, and South Africa, is a concerning finding. In Europe and the USA, practitioners are increasingly aware of the importance of infection control and antimicrobial stewardship. However, 50% of antimicrobials, irrespective of setting, are used inappropriately.2,3 We agree that most increases in global antibiotic consumption are probably caused by inappropriate use and that coordinated efforts to improve antimicrobial use internationally are desperately needed

UV solar irradiance in observations and the NRLSSI and SATIRE-S models

Total solar irradiance and UV spectral solar irradiance have been monitored since 1978 through a succession of space missions. This is accompanied by the development of models aimed at replicating solar irradiance by relating the variability to solar magnetic activity. The NRLSSI and SATIRE-S models provide the most comprehensive reconstructions of total and spectral solar irradiance over the period of satellite observation currently available. There is persistent controversy between the various measurements and models in terms of the wavelength dependence of the variation over the solar cycle, with repercussions on our understanding of the influence of UV solar irradiance variability on the stratosphere. We review the measurement and modelling of UV solar irradiance variability over the period of satellite observation. The SATIRE-S reconstruction is consistent with spectral solar irradiance observations where they are reliable. It is also supported by an independent, empirical reconstruction of UV spectral solar irradiance based on UARS/SUSIM measurements from an earlier study. The weaker solar cycle variability produced by NRLSSI between 300 and 400 nm is not evident in any available record. We show that although the method employed to construct NRLSSI is principally sound, reconstructed solar cycle variability is detrimentally affected by the uncertainty in the SSI observations it draws upon in the derivation. Based on our findings, we recommend, when choosing between the two models, the use of SATIRE-S for climate studies

Antimicrobial Stewardship Program Prompts Increased and Earlier Infectious Diseases Consultation

A recent analysis demonstrated that infectious diseases (ID) specialty intervention was associated with decreased mortality and hospital readmission. These benefits were greatest if involvement occurred within two days of hospital admission. Antimicrobial stewardship programs should augment the services of an ID specialist team and promote formal consultation. Implementation of an antimicrobial stewardship program at the Providence Veterans Affairs Medical Center was associated with an increased number of consults (increase of 72.2%) and decreased time to consult (3.5 days sooner), which might also dramatically improve patient outcomes, including mortality and readmission rates

The Effects of Obesity on the Comparative Effectiveness of Linezolid and Vancomycin in Suspected Methicillin-Resistant \u3cem\u3eStaphylococcus aureus\u3c/em\u3e Pneumonia

Background: Methicillin-Resistant Staphylococcus aureus (MRSA) has become a leading cause of pneumonia in the United States and there is limited data on treatment outcomes in obese patients.We evaluated the effectiveness of linezolid compared to vancomycin for the treatment of MRSA pneumonia in a national cohort of obese Veterans. Methods: This retrospective cohort study included obese patients (body mass index ≥ 30) admitted to Veterans Affairs hospitals with MRSA-positive respiratory cultures and clinical signs of infection between 2002 and 2012. Patients initiating treatment with either vancomycin or linezolid, but not both, were selected for inclusion. Propensity matching and adjustment of Cox proportional hazards regression models quantified the effect of linezolid compared with vancomycin on time to hospital discharge, intensive care unit discharge, 30-day mortality, inpatient mortality, therapy discontinuation, therapy change, 30-day readmission, and 30-day MRSA reinfection. We performed sensitivity analyses by vancomycin Minimum Inhibitory Concentrations (MICs) and true trough levels. Results: We identified 101 linezolid and 2,565 vancomycin patients. Balance in baseline characteristics between the treatment groups was achieved within propensity score quintiles and between propensity matched pairs (76 pairs). No significant differences were observed for the outcomes assessed. Among patients with vancomycin MICs of ≤ 1 μg/mL, the linezolid group had a significantly lower mortality rate, increased length of hospital stay, and longer therapy duration. There were no differences between the linezolid and vancomycin MICs of ≥ 1.5 μg/ mL groups. Clinical outcomes among those with vancomycin trough concentrations of 15-20 mg/L were similar to patients treated with linezolid. Conclusions: In our real-world comparative effectiveness study among obese patients with suspected MRSA pneumonia, linezolid was associated with a significantly lower mortality rate as compared to the vancomycin-treated patients with lower vancomycin MICs. Further studies are needed to determine whether this beneficial effect is observed in other study populations

Vancomycin Dosing Considerations in a Real-World Cohort of Obese and Extremely Obese Patients

Study Objective: To compare the effects of empiric vancomycin dosing regimens on attainment of optimal target trough concentrations in obese (body mass index [BMI] 30–40 kg/m2) and extremely obese (BMI ≥ 40 kg/m2) patients. Design: Retrospective cohort study. Data Source: National Veterans Affairs standardized databases. Patients: A total of 263 obese and 71 extremely obese (actual body weight range 72–244 kg in both groups) inpatients from all Veterans Affairs facilities nationally who had suspected methicillin-resistant Staphylococcus aureus pneumonia and were treated with vancomycin between 2002 and 2012. Measurements and Main Results: Patients with steady-state trough concentrations (measured ≤ 2 hours before the next vancomycin dose) and no evidence of acute kidney injury before vancomycin initiation were included. Logistic regression models were used to measure the effect of various vancomycin dosing regimens on attainment of optimal target trough concentrations (15–20 mg/L). The mean total daily vancomycin dose was lower in obese versus extremely obese patients (2005 ± 736 vs 2306 ± 934 mg, p Conclusion: In this real-world study, we offer additional consideration of vancomycin dosing in obese and extremely obese patients. Extremely obese patients may require a lower weight-based daily dose than obese patients to reach target vancomycin trough concentrations

Predictors of Mortality Among U.S. Veterans With \u3cem\u3eStreptococcus Pneumoniae\u3c/em\u3e Infections

Introduction Serious Streptococcus pneumoniae infections, encompassing pneumonia, bacteremia, and meningitis, are a major cause of mortality. However, literature regarding mortality is often limited to invasive pneumococcal disease, excluding pneumonia. This study sought to identify predictors of mortality among adults with serious pneumococcal disease, including pneumonia and invasive pneumococcal disease. Methods This was a nested case-control study of unvaccinated older Veterans with positive S. pneumoniae cultures (blood, cerebrospinal fluid, respiratory) admitted to Veterans Affairs medical centers nationally between 2002 and 2011. Patients vaccinated against pneumococcal disease were excluded. Using multivariable logistic regression, predictors of 30-day mortality were identified, including patient demographics, comorbidities during admission, and medical history within the previous year. Results Among 9,468 patients, there were 9,730 serious pneumococcal infections; 1,764 (18.6%) resulted in death within 30 days (cases), whereas 7,966 did not (controls). Pneumonia accounted for half (49.4%, n=871) of all deaths. Mortality predictors consistent with vaccine recommendations included dialysis (during hospitalization, OR=3.35, 95% CI=2.37, 4.72), moderate to severe liver disease (during hospitalization, OR=2.47, 95% CI=1.53, 3.99; within 1 year, OR=1.49, 95% CI=1.01, 2.20), and neutropenia (during hospitalization, OR=2.67, 95% CI=1.32, 5.42). Predictors not included in current recommendations included dementia (during hospitalization, OR=1.8, 95% CI=1.23, 2.61) and neurologic disorders (during hospitalization, OR=1.86, 95% CI=1.42, 2.45; within 1 year, OR=1.28, 95% CI=1.02, 1.59). Conclusions Several mortality predictors among unvaccinated Veterans with serious pneumococcal disease were consistent with pneumococcal vaccine recommendations, including organ or immune system dysfunction–related conditions. Other predictors, including neurologic disorders or dementia, may warrant expanded vaccination recommendations

Treatment Options for Carbapenem-Resistant Enterobacteriaceae Infections

This article provides a comprehensive review of currently available treatment options for infections due to carbapenem-resistant Enterobacteriaceae (CRE). Antimicrobial resistance in Gram-negative bacteria is an emerging and serious global public health threat. Carbapenems have been used as the “last-line” treatment for infections caused by resistant Enterobacteriaceae, including those producing extended spectrum ß-lactamases. However, Enterobacteriaceae that produce carbapenemases, which are enzymes that deactivate carbapenems and most other ß-lactam antibiotics, have emerged and are increasingly being reported worldwide. Despite this increasing burden, the most optimal treatment for CRE infections is largely unknown. For the few remaining available treatment options, there are limited efficacy data to support their role in therapy. Nevertheless, current treatment options include the use of older agents, such as polymyxins, fosfomycin, and aminoglycosides, which have been rarely used due to efficacy and/or toxicity concerns. Optimization of dosing regimens and combination therapy are additional treatment strategies being explored. Carbapenem-resistant Enterobacteriaceae infections are associated with poor outcomes and high mortality. Continued research is critically needed to determine the most appropriate treatment

Predictors of Clinical Success Among a National Veterans Affairs Cohort With Methicillin-Resistant Staphylococcus aureus Pneumonia

Background: The treatment of methicillin-resistant Staphylococcus aureus (MRSA) pneumonia is exceedingly complicated, which is concerning because of the high mortality rate associated with the infection. Identification of independent predictors of clinical success can optimize patient care by assisting clinicians in treatment decisions. Objectives: We sought to identify independent predictors of clinical success in a national Veterans Affairs (VA) cohort of MRSA pneumonia patients. Methods: A nested case-control study was conducted among a cohort of VA patients with MRSA pneumonia receiving linezolid or vancomycin between January 2002 and September 2010. Cases included those demonstrating clinical success, defined as discharge from the hospital or intensive care unit (ICU) by day 14 after treatment initiation, in the absence of death, therapy change, or intubation by day 14. Controls represented non-success, defined as therapy change, intubation, ICU admission, re-admission, or death between treatment initiation and day 14. The potential predictors assessed included treatment, patient demographics and admission characteristics, previous healthcare and medication exposures, comorbidities, and medical history. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated from logistic regression. Results: Our study included 2442 cases of clinical success and 1290 controls. Demographics varied between the clinical success and non-success groups, including age, race, and region of facility. A current diagnosis of chronic respiratory disease (46% vs 42%) and diagnosis of pneumonia in the year prior to the MRSA pneumonia admission (37% vs 32%) were both more common in the clinical success group. Despite these significant differences, only two predictors of clinical success were identified in our study: previous complication of an implant or graft, including mechanical complications and infections, in the year prior to the MRSA pneumonia admission (OR, 1.55; 95% CI, 1.17–2.06) and treatment with linezolid (1.53; 1.12–2.10). Predictors of non-success included concomitant urinary tract infection diagnosis (OR, 0.82; 95% CI, 0.70–0.96), intravenous line (0.76; 0.66–0.89), previous coagulopathy (0.74; 0.56–0.96), previous amputation procedure (0.72; 0.53–0.98), current coagulopathy diagnosis (0.71; 0.53–0.96), dialysis (0.54; 0.38–0.76), multiple inpatient procedures (0.53; 0.45–0.62), inpatient surgery (0.48; 0.41–0.57), and previous endocarditis (0.24; 0.07–0.81). Discussion: MRSA pneumonia tends to affect complex patients, and identification of the predictors of clinical success is useful when considering different therapeutic approaches. Conclusions: In a national cohort of VA patients with MRSA pneumonia, treatment was the only modifiable variable predicting clinical success

Antimicrobial Stewardship in Long-Term Care Facilities: A Call to Action

Antimicrobial resistance is a global public health crisis and a national security threat to the United States, as stated in an executive order signed by the president in September 2014. This crisis is a result of indiscriminant antimicrobial use, which promotes selection for resistant organisms, increases the risk of adverse drug events, and renders patients vulnerable to drug-resistant infections. Antimicrobial stewardship is a key measure to combat antimicrobial resistance and specifically seeks to do this by improving antimicrobial use. Antimicrobial stewardship compliments infection control practices and it is important to note that these 2 disciplines are distinct and cannot be discussed interchangeably. Antimicrobial stewardship promotes the appropriate diagnosis, drug, dose, and duration of treatment. The appropriate diagnosis falls into the hands of the prescriber and clinical staff. Optimal antimicrobial drug selection, dosing strategy, and duration of treatment, however, often require expertise in antimicrobial therapy, such as an infectious disease–trained physician or pharmacist. Therefore, successful antimicrobial stewardship programs must be comprehensive and interdisciplinary. Most antimicrobial stewardship programs focus on hospitals; yet, in long-term care, up to 75% of antimicrobial use is inappropriate or unnecessary. Thus, one of the most pressing areas in need for antimicrobial stewardship is in long-term care facilities. Unfortunately, there is little evidence that describes effective antimicrobial stewardship interventions in this setting. This review discusses the need for and barriers to antimicrobial stewardship in long-term care facilities. Additionally, this review describes prior interventions that have been implemented and tested to improve antimicrobial use in long-term care facilities

Bicyclic Boronate β-Lactamase Inhibitors: The Present Hope against Deadly Bacterial Pathogens

The use of β-lactamase inhibitors in combination with β-lactam antibiotics is an emerging area in drug discovery. This strategy allows the restoration of the therapeutic efficacy of these antibiotics in clinical use against multiresistant bacteria. These pathogens are drug resistant because they express β-lactamase enzymes, which prevent the antibiotic therapeutic action by catalyzing the hydrolysis of the β-lactam ring. These enzymes are quite diverse in both their structural architecture and hydrolytic capability, as well as in the mechanism of action. The ever-increasing emergence of pathogens that are capable of coproducing different types of β-lactamases has triggered the search for ultrabroad-spectrum inhibitors capable of deactivating both serine- and metallo-β-lactamases. A recent breakthrough in this long-pursued and unmet need is the discovery of bicyclic boronate inhibitors, specifically taniborbactam, VNRX-7145, and QPX7728, which are currently under clinical development in combination with cefepime, ceftibuten, and QPX2014, respectively. The present article highlights the therapeutic potential of these inhibitors and their spectrum of efficacy is compared with those of other β-lactam/β-lactamase inhibitor combinations recently approved by the food and drug administration. The molecular basis of the ultrabroad-spectrum of activity of boron-based inhibitors is also discussed, on the basis of the available crystal structures and the results of computational studiesinancial support from the Spanish Ministry of Economy and Competiveness (SAF2016-75638-R, PID2019-105512RB-I00), the Xunta de Galicia [ED431B 2018/04 and Centro singular de investigación de Galicia accreditation 2019–2022 (ED431G 2019/03)], and the European Regional Development Fund (ERDF) is gratefully acknowledgedS