Ventilator-associated pneumonia (VAP) is one of the most common hospital-acquired infections in ICUs and is associated with significant morbidity and mortality. Gram-negative bacteria cause 55-85% of ...hospital-acquired pneumonia and are associated with increased mortality.
This study sought to describe mortality rates and 30-d readmission rates among intubated and mechanically ventilated subjects with Gram-negative pneumonia and to explore associated risk factors for mortality and rehospitalization using data from the 2013 Healthcare Cost and Utilization Project (HCUP) National Readmission Database. The study sample included adults age ≥ 18 y who were hospitalized with invasive, continuous mechanical ventilation; were discharged between February 1, 2013, and November 30, 2013; and had a primary or secondary diagnosis of Gram-negative bacterial pneumonia. Logistic regression was used to identify subject characteristics significantly associated with mortality and readmissions.
Using the HCUP projected sample of 32,683 intubated and mechanically ventilated subjects with Gram-negative pneumonia, the mortality rate during the index hospitalization was 24.3%. More than one fifth of subjects (22.9%) who survived the index hospitalization were readmitted within 30 d of discharge. Among subjects with readmissions, 18% occurred within 3 d of discharge, 39% occurred within 7 d of discharge, and 65% occurred within 14 d of discharge. Subjects with prior hospitalization within 30 d of the index hospitalization had a higher risk of readmission with an odds ratio of 1.70 (95% CI 1.48-1.94).
Mortality was high and readmissions were substantial among intubated and mechanically ventilated subjects with Gram-negative pneumonia.
The revised vancomycin consensus guidelines recommended area under the curve (AUC)-guided dosing/monitoring for patients with serious invasive methicillin-resistant Staphylococcus aureus (MRSA) ...infections as a measure to minimize vancomycin-associated acute kidney injury (VA-AKI) while maintaining similar effectiveness. Data indicate that the intensity of vancomycin exposure drives VA-AKI risk. Troughs of 15-20 mg/L will ensure an AUC ≥400 mg × hr/L but most patients will have daily AUCs >600. VA-AKI increases as a function of AUC, especially when >600. In addition to minimizing VA-AKI risk while maintaining similar efficacy, AUC-guided dosing/monitoring is a more precise way to conduct therapeutic drug monitoring for vancomycin relative to trough-only control.
This review critically appraises the published microbiologic and clinical data on the treatment of patients with carbapenem-resistant Acinetobacter baumannii infections. Despite being recognized as ...an urgent threat pathogen by the CDC and WHO, optimal treatment of patients with serious CRAB infections remains ill-defined. Few commercially available agents exhibit reliable in vitro activity against CRAB. Historically, polymyxins have been the most active agents in vitro, though interpretations of susceptibility data are difficult given issues surrounding MIC testing methodologies and lack of correlation between MICs and clinical outcomes. Most available preclinical and clinical data involve use of polymyxins, tetracyclines, and sulbactam, alone and in combination. As the number of viable treatment options is limited, combination therapy with a polymyxin is often used for patients with CRAB infections, despite the significant risk of nephrotoxicity. However, no treatment regimen has been found to reduce mortality, which exceeds 40% across most studies, or substantially improve clinical response. While some newer agents, such as eravacycline and cefiderocol, have demonstrated in vitro activity, clinical efficacy has not been fully established. New agents with clinically relevant activity against CRAB isolates and favorable toxicity profiles are sorely needed.
Tedizolid, a novel oxazolidinone with activity against a wide range of Gram-positive pathogens, was evaluated in two noninferiority phase 3 acute bacterial skin and skin structure infection trials. ...The data from individual trials showed its noninferior efficacy compared to that of linezolid and a favorable tolerability profile. To evaluate potential differences, the pooled data were analyzed. The patients received 200 mg of tedizolid once daily for 6 days or 600 mg of linezolid twice daily for 10 days. Efficacy was evaluated at 48 to 72 h (primary endpoint), on days 11 to 13 (end of therapy EOT), and 7 to 14 days after the EOT (posttherapy evaluation). Treatment-emergent adverse events and hematologic and clinical laboratory parameters were collected. The baseline characteristics were comparable between the treatment groups: 852/1,333 (64%) patients were from North America, and the majority of infections were caused by Staphylococcus aureus. Tedizolid was noninferior to linezolid (early clinical responses, 81.6% versus 79.4%, respectively). The early responses remained relatively consistent across various host/disease factors and severity measures. Nausea was the most frequently reported adverse event (tedizolid, 8.2%; linezolid, 12.2%; P=0.02), with onset occurring primarily during the first 6 days. Fewer tedizolid than linezolid patients had platelet counts of <150,000 cells/mm3 at the EOT (tedizolid, 4.9%; linezolid, 10.8%; P=0.0003) and during the postbaseline period through the last day of active drug visit (tedizolid, 6.4%; linezolid, 12.6%; P=0.0016). Efficacy was achieved with a 6-day once-daily course of therapy with the option of an intravenous/oral regimen, and fewer low platelet counts and gastrointestinal side effects were reported with tedizolid than with linezolid, all of which aligns well with antimicrobial stewardship principles. (These studies have been registered at ClinicalTrials.gov under registration no. NCT01170221 and NCT01421511.).
Oral tetracyclines have been used in clinical practice for over 60 years. One of the most common indications for use of oral tetracyclines is for treatment of adult outpatients with skin and soft ...infections (SSTIs), including acute bacterial skin and skin structure infections (ABSSSIs). The 2014 Infectious Diseases Society of America (IDSA) skin and soft tissue guideline strongly recommends sulfamethoxazole/trimethoprim, clindamycin, and tetracyclines as oral treatment options for patients with purulent SSTIs, especially when methicillin‐resistant Staphylococcus aureus is of clinical concern. Despite the long‐standing use of tetracyclines, practice patterns indicate that they are often considered after other guideline‐concordant oral options for the treatment of patients with SSTIs. Clinicians may therefore be less familiar with the clinical data associated with use of commercially available tetracycline agents for treatment of patients with SSTI. This review summarizes the literature on the use of oral tetracyclines (ie, doxycycline, minocycline, and omadacycline) for the treatment of adult patients with SSTIs. As part of this review, we describe their common mechanisms of resistance, susceptibility profiles against common SSTI pathogens, pharmacokinetics and pharmacodynamics, and comparative clinical data.
Abstract
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.
A multicenter prospective study was performed to evaluate the relationship between day 2 vancomycin exposure profiles and outcomes in patients with methicillin-resistant Staphylococcus aureus bacteremia. The collective findings suggest that vancomycin dosing should be guided by the area under the curve (AUC) and day 2 AUCs should be maintained between 400 and 515.
Therapeutic drug management is regularly performed for aminoglycosides in an effort to maximize their effectiveness and safety. The ratio of maximum plasma drug concentration to minimum inhibitory ...concentration (Cmax/MIC) has long been regarded as the primary pharmacokinetic/pharmacodynamic (PK/PD) index of clinical efficacy for aminoglycosides due to their concentration-dependent killing. In this review, however, we discuss why the area under the plasma concentration-time curve (AUC)/MIC ratio may be a more reliable indicator of bacterial killing and clinical efficacy for these agents. The definitive AUC/MIC efficacy targets for aminoglycosides are less clear, unlike those that exist for fluoroquinolones. Evaluation of available literature suggests that an AUC/MIC ratio of 30-50 for aminoglycoside therapy may provide optimal outcomes when targeting non-critically ill immunocompetent patients with low-bacterial burden gram-negative infections such as urinary tract infections or in patients receiving additional gram-negative therapy with good source control. However, an AUC/MIC target of 80-100 may be more prudent when treating patients with aminoglycoside monotherapy or in critically ill patients with high-bacterial burden infections, such as nosocomial pneumonia. Reappraisal of current antimicrobial susceptibility breakpoints for aminoglycosides against gram-negative bacteria may also be necessary to achieve these AUC/MIC targets and ensure that current empiric doses are not grossly suboptimal in critically ill patients. Although it has been historically difficult to calculate AUCs in clinical practice, equation-based and Bayesian approaches now can be used to estimate the AUC in clinical practice, with limited PK sampling. Additional research is needed to better define optimal AUC/MIC targets for efficacy, especially when drugs are used in combination, as well as PK/PD targets associated with suppression of resistance. It is also important to determine if AUC can predict nephrotoxicity of these agents or whether trough concentrations should be used instead.
Studies of the association between inappropriate antibiotic therapy and mortality among bacteremic patients have generated conflicting findings. We systematically reviewed these studies to identify ...methodological heterogeneity that may explain the lack of agreement. We identified 51 articles that met the inclusion criteria, and we extracted the following data: study design, definition and measurement of variables, and statistical methods. Only 8 studies (16%) defined inappropriate antibiotic therapy as that which was inactive in vitro against the isolated organism(s) and not consistent with current clinical practice recommendations and distinguished between empiric and definitive treatment. Thirty-four studies (67%) measured the severity of illness, but only 6 (12%) specified the time at which it was measured. The methodological recommendations suggested in this article are intended to improve the validity and generalizability of future research. In brief, future studies should define "inappropriate" therapy on the basis of in vitro susceptibility data, should separately evaluate empiric and definitive therapy, and should control for the baseline severity of illness.
Increasing antimicrobial resistance and medical device-related infections have led to a renewed interest in phage therapy as an alternative or adjunct to conventional antimicrobials. Expanded access ...and compassionate use cases have risen exponentially but have varied widely in approach, methodology, and clinical situations in which phage therapy might be considered. Large gaps in knowledge contribute to heterogeneity in approach and lack of consensus in many important clinical areas. The Antibacterial Resistance Leadership Group (ARLG) has convened a panel of experts in phage therapy, clinical microbiology, infectious diseases, and pharmacology, who worked with regulatory experts and a funding agency to identify questions based on a clinical framework and divided them into three themes: potential clinical situations in which phage therapy might be considered, laboratory testing, and pharmacokinetic considerations. Suggestions are provided as answers to a series of questions intended to inform clinicians considering experimental phage therapy for patients in their clinical practices.
PDF
