Steven W. Johnson

Utility of a clinical risk factor scoring model in predicting infection with extended-spectrum β-lactamase-producing enterobacteriaceae on hospital admission.

OBJECTIVE To validate the utility of a previously published scoring model (Italian) to identify patients infected with community-onset extended-spectrum β-lactamase-producing Enterobacteriaceae (ESBL-EKP) and develop a new model (Duke) based on local epidemiology. METHODS This case-control study included patients 18 years of age or more admitted to Duke University Hospital between January 1, 2008, and December 31, 2010, with culture-confirmed infection due to an ESBL-EKP (cases). Uninfected controls were matched to cases (3:1). The Italian model was applied to our patient population for validation. The Duke model was developed through logistic-regression-based prediction scores calculated on variables independently associated with ESBL-EKP isolation. Sensitivities and specificities at various point cutoffs were determined, and determination of the area under the receiver operating characteristic curve (ROC AUC) was performed. RESULTS A total of 123 cases and 375 controls were identified. Adjusted odds ratios and 95% confidence intervals for variables previously identified in the Italian model were as follows: hospitalization (3.20 [1.62-6.55]), transfer (4.31 [2.15-8.78]), urinary catheterization (5.92 [3.09-11.60]), β-lactam and/or fluoroquinolone therapy (3.76 [2.06-6.95]), age 70 years or more (1.55 [0.79-3.01]), and Charlson Comorbidity Score of 4 or above (1.06 [0.55-2.01]). Sensitivity and specificity were, respectively, more than or equal to 95% and less than or equal to 47% for scores 3 or below and were less than or equal to 50% and more than or equal to 96% for scores 8 or above. The ROC AUC was 0.88. Variables identified in the Duke model were as follows: hospitalization (2.63 [1.32-5.41]), transfer (5.30 [2.67-10.71]), urinary catheterization (6.89 [3.62-13.38]), β-lactam and/or fluoroquinolone therapy (3.47 [1.91-6.41]), and immunosuppression (2.34 [1.14-4.80]). Sensitivity and specificity were, respectively, more than or equal to 94% and less than or equal to 65% for scores 3 or below and were less than or equal to 58% and more than or equal to 95% for scores 8 or above. The ROC AUC was 0.89. CONCLUSION While the previously reported model was an excellent predictor of community-onset ESBL-EKP infection, models utilizing factors based on local epidemiology may be associated with improved performance.

Ongoing Pain Despite Aggressive Opioid Pain Management Among Persons With HIV

BackgroundChronic pain is a common problem among persons living with HIV and opioids are frequently used in its treatment. However, data on the variables associated with opioids use and the efficacy of this practice are lacking. MethodsWe performed a cross-sectional cohort study of self-reported pain during the year 2005 in our clinic. Patients were grouped into 3 cohorts: those receiving daily opioid therapy for chronic pain (cohort 1, n=115), those with a chronic pain diagnosis but not on daily opioid therapy (cohort 2, n=209), and those without a chronic pain diagnosis (cohort 3, n=796). ResultsIn multivariate analysis comparing cohorts 1 and 2, patients in cohort 1 were significantly more likely to be on a benzodiazepine or gamma-aminobutyric receptor agonist [odds ratio (OR)=15.2], have injection drug use as a HIV risk factor (OR=4.27), lack private insurance (OR=3.51), have been abused (OR=3.08), have a history of AIDS (OR=2.21), and be seen more frequently (OR=1.18). Patients in cohort 1 reported significantly more pain [mean pain scores (0 to 10): 4.3 cohort 1; 1.9 cohort 2; 0.7 cohort 3], and were more likely to have pain that was of moderate or greater severity (58.6% cohort 1; 15.5% cohort 2; 4.9% cohort 3). ConclusionsPsychosocial variables and a history of AIDS were associated with opioid use in our clinic. Persons on opioids continued to experience significantly more pain than other patients in our clinic.

Recent advances in the treatment of life-threatening, invasive fungal infections

Introduction: Invasive fungal infections (IFIs) pose significant morbidity and are often life-threatening to many high-risk patients. Timely diagnosis and treatment of these infections with optimal therapy is imperative. Areas covered: Advances have been made in diagnostic biomarkers such as peptide nucleic acid fluorescent in situ hybridization, β-D-glucan and galactomannan, although more research is needed in this area to assist with both diagnosis and monitoring for improvement of IFI management. Novel antifungal agents (azole antifungals and echinocandins) are being investigated that have activity against Candida spp. and Aspergillus spp. Optimizing the pharmacodynamics (PD) of our current antifungal therapies through such strategies as continuous infusion of amphotericin B and dose escalation of echinocandins and liposomal formulations of amphotericin B have also been investigated with mixed results. Therapeutic drug monitoring (TDM) shows promise as evident from data with such agents as flucytosine, itraconazole, voriconazole and posaconazole. Expert opinion: The goal for the future of biomarkers in IFIs will be to have excellent sensitivity and specificity to ideally identify a particular fungus causing the infection or eliminate its existence to prevent unnecessary costs, resistance and antifungal usage. In addition, further developments of new antifungals are needed and judicious use of the current regimens needs to be optimized through antifungal PD properties and TDM.

Role of isavuconazole in the treatment of invasive fungal infections.

Despite recent advances in both diagnosis and prevention, the incidence of invasive fungal infections continues to rise. Available antifungal agents to treat invasive fungal infections include polyenes, triazoles, and echinocandins. Unfortunately, individual agents within each class may be limited by spectrum of activity, resistance, lack of oral formulations, significant adverse event profiles, substantial drug–drug interactions, and/or variable pharmacokinetic profiles. Isavuconazole, a second-generation triazole, was approved by the US Food and Drug Administration in March 2015 and the European Medicines Agency in July 2015 for the treatment of adults with invasive aspergillosis (IA) or mucormycosis. Similar to amphotericin B and posaconazole, isavuconazole exhibits a broad spectrum of in vitro activity against yeasts, dimorphic fungi, and molds. Isavuconazole is available in both oral and intravenous formulations, exhibits a favorable safety profile (notably the absence of QTc prolongation), and reduced drug–drug interactions (relative to voriconazole). Phase 3 studies have evaluated the efficacy of isavuconazole in the management of IA, mucormycosis, and invasive candidiasis. Based on the results of these studies, isavuconazole appears to be a viable treatment option for patients with IA as well as those patients with mucormycosis who are not able to tolerate or fail amphotericin B or posaconazole therapy. In contrast, evidence of isavuconazole for invasive candidiasis (relative to comparator agents such as echinocandins) is not as robust. Therefore, isavuconazole use for invasive candidiasis may initially be reserved as a step-down oral option in those patients who cannot receive other azoles due to tolerability or spectrum of activity limitations. Post-marketing surveillance of isavuconazole will be important to better understand the safety and efficacy of this agent, as well as to better define the need for isavuconazole serum concentration monitoring.

Variables associated with decreasing pain among persons living with human immunodeficiency virus: a longitudinal follow-up study.

BackgroundPain is common among persons with human immunodeficiency virus (HIV); however, there are minimal data on its natural history, or the long-term efficacy of analgesic therapies. MethodsWe performed an observational study between 2001 and 2009. Pain was defined on a 0 to 10 scale; 0=no pain; 10=worst pain possible. Patients were included if they were HIV positive, had a chronic pain diagnosis, a median pain score during the first year of observation of ≥1.0, ≥2 years of follow-up, and ≥3 recorded pain scores. Two models were used to describe decreasing pain. Model 1 defined decreasing pain as a negative slope to the best fit line through all recorded pain scores. Model 2 defined decreasing pain as a median pain score of zero during the last year of follow-up. ResultsUsing model 1, decreasing pain was negatively associated with a history of being abused (odds ratio=0.29) and positively associated with peripheral neuropathy (3.54). Using model 2, decreasing pain was positively associated with highly active antiretroviral therapy (3.71) and negatively associated with opioid analgesic use (0.24). ConclusionsWe found social and HIV-related variables associated with decreasing pain. We failed to show a positive association between analgesic use and decreasing pain.

Hepatitis C Virus-Genotype 3: Update on Current and Emergent Therapeutic Interventions

Purpose of ReviewDirect-acting antiviral agents (DAAs) have markedly improved the prognosis of hepatitis C virus (HCV)-genotype 3 (GT3), a highly prevalent infection worldwide. However, in patients with hepatic fibrosis, cirrhosis, or hepatocellular carcinoma (HCC), GT3 infection presents a treatment challenge compared with other genotypes. The dependence of the HCV life cycle on host lipid metabolism suggests the possible utility of targeting host cellular factors for combination anti-HCV therapy. We discuss current and emergent DAA regimens for HCV-GT3 treatment. We then summarize recent research findings on the reliance of HCV entry, replication, and virion assembly on host lipid metabolism.Recent FindingsCurrent HCV treatment guidelines recommend the use of daclatasvir plus sofosbuvir (DCV/SOF) or sofosbuvir plus velpatasvir (SOF/VEL) for the management of GT3 based upon clinical efficacy [≥88% overall sustained virological response (SVR)] and tolerability. Potential future DAA options, such as SOF/VEL co-formulated with GS-9857, also look promising in treating cirrhotic GT3 patients. However, HCV resistance to DAAs will likely continue to impact the therapeutic efficacy of interferon-free treatment regimens. Disruption of HCV entry by targeting required host cellular receptors shows potential in minimizing HCV resistance and broadening therapeutic options for certain subpopulations of GT3 patients. The use of cholesterol biosynthesis and transport inhibitors may also improve health outcomes for GT3 patients when used synergistically with DAAs.SummaryDue to the morbidity and mortality associated with HCV-GT3 infection compared to other genotypes, efforts should be made to address current limitations in the therapeutic prevention and management of HCV-GT3 infection.

Clinical impact of switching conventional enzyme immunoassay with nucleic acid amplification test for suspected Clostridium difficile-associated diarrhea

The impact of a new Clostridium difficile nucleic acid amplification test (NAAT) on antibiotic utilization in patients with suspected C difficile infection was assessed. This single-center, cross-sectional study of 270 patients demonstrated that the use of NAAT decreased antibiotic expenditure by reducing prolonged empiric days of therapy in these patients.

How long to treat with antibiotics following amputation in patients with diabetic foot infections? Are the 2012 IDSA DFI guidelines reasonable?

To the best of our knowledge, there has been no published study designed to identify the most appropriate duration of antibiotic therapy in lower extremity skin and skin structure infections in diabetic patients [aka “diabetic foot infections” (DFI)] post‐amputation. However, recent guidelines published by the Infectious Diseases Society of America (IDSA) provide recommendations for treatment duration in these patients. Therefore, our objective is to review the literature evaluating antibiotic treatment in DFI to determine if the IDSA guidelines are reasonable.

Focus on JNJ-Q2, a novel fluoroquinolone, for the management of community-acquired bacterial pneumonia and acute bacterial skin and skin structure infections

JNJ-Q2 is a novel, fifth-generation fluoroquinolone that has excellent in vitro and in vivo activity against a variety of Gram-positive and Gram-negative organisms. In vitro studies indicate that JNJ-Q2 has potent activity against pathogens responsible for acute bacterial skin and skin structure infections (ABSSSI) and community-acquired bacterial pneumonia (CABP), such as Staphylococcus aureus and Streptococcus pneumoniae. JNJ-Q2 also has been shown to have a higher barrier to resistance compared to other agents in the class and it remains highly active against drug-resistant organisms, including methicillin-resistant S. aureus, ciprofloxacin-resistant methicillin-resistant S. aureus, and drug-resistant S. pneumoniae. In two Phase II studies, the efficacy of JNJ-Q2 was comparable to linezolid for ABSSSI and moxifloxacin for CABP. Furthermore, JNJ-Q2 was well tolerated, with adverse event rates similar to or less than other fluoroquinolones. With an expanded spectrum of activity and low potential for resistance, JNJ-Q2 shows promise as an effective treatment option for ABSSSI and CABP. Considering its early stage of development, the definitive role of JNJ-Q2 against these infections and its safety profile will be determined in future Phase III studies.

Cure with ledipasvir/sofosbuvir for chronic hepatitis C virus in an individual with gastric bypass

The impact of gastric bypass surgery on the pharmacokinetics of various medications has been reported. Presently, no data exist for the treatment of chronic hepatitis C virus with ledipasvir/sofosbuvir (LDV/SOF) in an individual with a history of gastric bypass.