Population Pharmacokinetics of Piperacillin/Tazobactam Across the Adult Lifespan.

BACKGROUND AND OBJECTIVE: Piperacillin/tazobactam is one of the most frequently used antimicrobials in older adults. Using an opportunistic study design, we evaluated the pharmacokinetics of piperacillin/tazobactam as a probe drug to evaluate changes in antibacterial drug exposure and dosing requirements, including in older adults. METHODS: A total of 121 adult patients were included. The population pharmacokinetic models that best characterized the observed plasma concentrations of piperacillin and tazobactam were one-compartment structural models with zero-order input and linear elimination. RESULTS: Among all potential covariates, estimated creatinine clearance had the most substantial impact on the elimination clearance for both piperacillin and tazobactam. After accounting for renal function and body size, there was no remaining impact of frailty on the pharmacokinetics of piperacillin and tazobactam. Monte Carlo simulations indicated that renal function had a greater impact on the therapeutic target attainment than age, although these covariates were highly correlated. Frailty, using the Canadian Study of Health and Aging Clinical Frailty Scale, was assessed in 60 patients who were ≥ 65 years of age. CONCLUSIONS: The simulations suggested that adults ≤ 50 years of age infected with organisms with higher minimum inhibitory concentrations may benefit from continuous piperacillin/tazobactam infusions (12 g/day of piperacillin component) or extended infusions of 4 g every 8 hours. However, for a target of 50% fT + minimum inhibitory concentration, dosing based on renal function is generally preferable to dosing by age, and simulations suggested that patients with creatinine clearance ≥ 120 mL/min may benefit from infusions of 4 g every 8 hours for organisms with higher minimum inhibitory concentrations.

Evaluating the effect and user satisfaction of an adapted and translated mobile health application ASTHMAXcel© among adults with asthma in Pune, India.

OBJECTIVE: ASTHMAXcel© is a mobile application previously shown to improve asthma knowledge, control, and quality of life. In this study, we translated the application to Marathi for pilot testing in Pune, India in order to evaluate its impact on user satisfaction and asthma knowledge among adult asthma patients. METHODS: ASTHMAXcel© was adapted to Marathi with the help of asthma patients and clinicians from Bharati Hospital. 57 different asthma patients were then recruited and received the Asthma Knowledge Questionnaire (AKQ), Asthma Control Questionnaire (ACQ), and Mini Asthma Quality of Life Questionnaire (Mini-AQLQ) to complete at baseline. Study participants then completed the adapted ASTHMAXcel© application. Post-intervention, participants filled out a post-AKQ and Questionnaire for User Interface Satisfaction (QUIS). A subset of participants was also interviewed for qualitative feedback. Paired t-tests and Pearson's correlation were used for statistical analysis. RESULTS: Mean AKQ improved from 5.0+/-2.4 to 12.4+/-1.6 (p = 0.0001). QUIS results revealed that participants were highly satisfied with the application, scoring an average of 50 out of 54 maximum points. Better baseline asthma control was correlated with greater overall experience with the application (-0.110, p = 0.0417). Finally, the qualitative feedback revealed four themes for future refinement. CONCLUSION: The adapted version of ASTHMAXcel© was linked to significant improvement in patient asthma knowledge and a high level of user satisfaction. These results support the potential utility of mHealth applications in promoting guideline-based asthma care in India. However, further studies are needed to establish a causal relationship between ASTHMAXcel© and improved clinical outcomes.

Young-onset colon cancer among people living with HIV in metropolitan Atlanta.

PURPOSE: Colon cancer is a leading cause of cancer-related morbidity and mortality in the USA. We sought to better characterize colon cancer among a predominantly Black cohort with and without HIV. METHODS: We retrospectively reviewed all patients (n = 1482) diagnosed with colon cancer between 2015 and 2019 at a large urban tertiary teaching hospital using ICD-9 and ICD-10 codes. In this cohort, 114 (7.7%) of the patients also had HIV. Descriptive summaries were performed for gender, age, race/ethnicity, insurance status, tobacco/alcohol use, and BMI. RESULTS: Among patients with colon cancer only, 50.51% (n = 691) were men and 49.49% (n = 677) were women. Among patients with both HIV and colon cancer, 78.95% (n = 90) were men and 21.05% (n = 24) were women (p-value < 0.001). The mean age of the colon cancer patient sample was 61.62 years for those without HIV and 51.31 years for those with HIV (p-value < 0.001). Persons with both HIV and colon cancer were more likely to have a lower BMI (p-value < 0.001) and a history of smoking and alcohol use (p-value < 0.001), compared to patients with colon cancer only. When accounting for BMI, tobacco, and alcohol use, those with HIV were 10 years younger than those without HIV, 95% CI, 7.3-13; p < 0.001. CONCLUSIONS: In this study, HIV positive status was a risk factor for developing colon cancer at a younger age. Larger observational studies with multivariable analysis should be done to better describe the risk of colon cancer and HIV.

Proton pump inhibitor usage reduces sustained viral response rates for veterans with HIV/HCV coinfection on ledipasvir/sofosbuvir: a real-world study from a multicentre VA cohort.

Previous studies have reported an association of proton pump inhibitor (PPI) use and decreased sustained viral response rate (SVR) in patients taking ledipasvir/sofosbuvir (LDV/SOF). The relationship between PPI usage and SVR is less clear in patients with HIV/HCV coinfection, where concomitant antiretrovirals may result in more complex drug interactions. This retrospective study evaluates the effects of acid suppression medications (PPI or H2 -receptor antagonist [H2 B]) use and SVR rates in patients with HIV/HCV or HCV and taking LDV/SOF in a large multicentre veteran cohort. Patients in the Veterans Affairs Health Care System who received LDV/SOF ± ribavirin from 10/10/2014 to 12/31/2015 were included. The odds ratios (OR) of PPI or H2 B use for SVR were adjusted for clinical factors and with inverse probability of treatment weighting for non-random treatment selection for acid suppression medication use. There were 9703 veterans included in our final analysis. After adjustment of other clinical factors, PPI use is associated with a lower SVR in the overall cohort (95.0% vs. 96.1%, OR: 0.86, 95% CI: 0.74-0.99, p = .03, number needed to harm 90.9) and HIV/HCV coinfection subgroup (93.4% vs. 96.9%, OR: 0.47, 95% CI: 0.26-0.85, p = .01, number needed to harm 28.6). This present study reveals PPI use is associated with reduced SVR after LDV/SOF treatment, with a more significant impact in the subgroup of patients with HIV/HCV coinfection. Precautions need to be taken when using PPI and LDV/SOF in this group of patients.

Corrigendum to "Outcomes of Programmed Cell Death Protein 1 (PD-1) and Programmed Death-Ligand 1 (PD-L1) Inhibitor Therapy in HIV Patients with Advanced Cancer".

[This corrects the article DOI: 10.1155/2019/2989048.].

Outcomes of Programmed Cell Death Protein 1 (PD-1) and Programmed Death-Ligand 1(PD-L1) Inhibitor Therapy in HIV Patients with Advanced Cancer.

Due to HAART and consequent decline in mortality from infectious complications, HIV patients have an increasing burden of non-AIDS defining cancers. Data on their safety and efficacy is unknown as these patients were excluded from clinical trials due to concern of unforeseen side effects. Objectives. The main objective of our study was to evaluate the efficacy and safety profile of PD-1 and PD-L1 inhibitors in HIV patients being treated for advanced cancers and to assess the impact of these drugs on HIV status of the patients specifically CD4 count and HIV viral load. Materials and Methods. This was a retrospective analysis of data of 17 patients HIV treated with one of the PD-1/PD-L1 inhibitors (Nivolumab, Pembrolizumab, Atezolizumab, Durvalumab, or Avelumab) for advanced cancer. Results. 10 out of 17 patients responded to therapy. 7 patients, all of whom had shown response to therapy, were alive and 4 were still on checkpoint inhibitor. 10 patients including all 7 nonresponders had died. Responders had minimum of 15 weeks of response while one had ongoing continued response at 34 weeks. Side effects were seen in 7 patients and only one patient needed cessation of therapy. CD4 counts were stable on treatment while HIV RNA remained undetectable. Conclusion. PD-1 and PD-L1 inhibitors appear to have comparable efficacy and tolerable side effect profile and have no effect on HIV markers when used in HIV patients with advanced cancers.

Correlation Between Tenofovir Drug Levels and the Renal Biomarkers RBP-4 and ß2M in the ION-4 Study Cohort.

BACKGROUND: Concomitant dosing of ledipasvir (LDV) and tenofovir disoproxil fumarate (TDF) results in an increased tenofovir (TFV) area under the curve (AUC). The aim of this study was to examine whether there was a correlation between the renal biomarkers retinol binding protein-4 (RBP-4) and ß2 microglobulin (ß2M) and tenofovir AUC. METHODS: The ION-4 trial enrolled HIV/hepatitis C virus-coinfected patients on nonpharmacologically boosted antiretroviral regimens with TDF-containing backbones. We assessed for a correlation between tenofovir AUC and urinary biomarkers and also for changes in serologic biomarkers with respect to clinically relevant changes in renal function (creatinine clearance decrease >25%, change in creatinine >0.2 mg/dL, change in proteinuria from negative/trace to ≥1+). RESULTS: Three hundred thirty-five patients were enrolled in the ION-4 study; their demographic characteristics have been previously described. Both RBP-4 and ß2M exhibited positive correlations with tenofovir AUC. Baseline and study levels of RBP-4 and ß2M were higher for patients with increases in urine proteinuria and an absolute creatinine increase. CONCLUSIONS: TFV exposure is associated with increased proximal tubule urine biomarkers in participants on ledipasvir/sofosbuvir and nonpharmacologically boosted TDF-based antiretroviral regimens. Baseline proximal tubule biomarkers may predict nephrotoxicity risk if events are prevalent. Further studies assessing the predictive role of these urine biomarkers may help guide medical decision-making and risk/benefit assessments in patients with risk factors for renal dysfunction.

Candida dubliniensis abscess: A clinical case and a review of the literature.

Candida dubliniensis infections are rare in the absence of prolonged immunocompromised status or intravenous drug abuse. We present a case of a C. dubliniensis soft tissue abscess in a patient with uncontrolled diabetes as his only immunocompromising risk factor, treated with surgical drainage and medical management.

Direct-Acting Antivirals Improve Access to Care and Cure for Patients With HIV and Chronic HCV Infection.

BACKGROUND: Direct-acting antivirals (DAA) as curative therapy for hepatitis C virus (HCV) infection offer >95% sustained virologic response (SVR), including in patients with human immunodeficiency virus (HIV) infection. Despite improved safety and efficacy of HCV treatment, challenges remain, including drug-drug interactions between DAA and antiretroviral therapy (ART) and restrictions on access by payers. METHODS: We performed a retrospective cohort study of all HIV/HCV co-infected and HCV mono-infected patients captured in care at our institution from 2011-2015, reflecting the DAA era, to determine treatment uptake and SVR, and to elucidate barriers to accessing DAA for co-infected patients. RESULTS: We identified 9290 patients with HCV mono-infection and 507 with HIV/HCV co-infection. Compared to mono-infected patients, co-infected patients were younger and more likely to be male and African-American. For both groups, treatment uptake improved from the DAA/pegylated interferon (PEGIFN)-ribavirin to IFN-free DAA era. One-third of co-infected patients in the IFN-free DAA era required ART switch and nearly all remained virologically suppressed after 6 months. We observed SVR >95% for most patient subgroups including those with co-infection, prior treatment-experience, and cirrhosis. Predictors of access to DAA for co-infected patients included Caucasian race, CD4 count ≥200 cells/mm3, HIV virologic suppression and cirrhosis. Time to approval of DAA was longest for patients insured by Medicaid, followed by private insurance and Medicare. CONCLUSIONS: DAA therapy has significantly improved access to HCV treatment and high SVR is independent of HIV status. However, in order to realize cure for all, barriers and disparities in access need to be urgently addressed.

Genotype 3 Infection: The Last Stand of Hepatitis C Virus.

Hepatitis C virus (HCV) represents a significant global disease burden, with an estimated 130-150 million people worldwide living with chronic HCV infection. Within the six major clinical HCV genotypes, genotype 3 represents 22-30% of all infection and is described as a unique entity with higher rates of steatosis, faster progression to cirrhosis, and higher rates of hepatocellular carcinoma. Hepatic steatosis in the setting of hepatitis C genotype 3 (HCV-3) is driven by viral influence on three major pathways: microsomal triglyceride transfer protein, sterol regulatory element-binding protein-1c, and peroxisome proliferator-associated receptor-α. Historically with direct-acting antivirals, the rates of cure for HCV-3 therapies lagged behind the other genotypes. As current therapies for HCV-3 continue to close this gap, it is important to be cognizant of common drug interactions such as acid-suppressing medication and amiodarone. In this review, we discuss the rates of steatosis in HCV-3, the mechanisms behind HCV-3-specific steatosis, and current and future therapies.

Risk factors and epidemiology of Clostridium difficile infection in hematopoietic stem cell transplant recipients during the peritransplant period.

BACKGROUND: Hematopoietic stem cell transplant (HSCT) recipients represent a high-risk group for developing Clostridium difficile (CD) infection (CDI). We aimed to identify specific risk factors for CDI in an HSCT patient population during the peritransplant period. METHODS: We performed a case-control study within a cohort of HSCT patients who received a transplant from November 2010 to March 2013. Cases had a clinical presentation compatible with CDI and a positive stool sample Xpert® C. difficile test. Controls were CDI negative and matched on age, gender, and transplant type. Peritransplant period was defined as -30 days or time of stem cell mobilization maneuver to 30 days post transplant in autologous SCT or 90 days post transplant in allogeneic SCT. RESULTS: Of 781 HSCTs performed during the study period, 650 (83.2%) had a stool sample submitted for CD testing. Eight-six (13.2%) cases with CDI were identified. Most of the cases were diagnosed within a week after transplantation (median of 5 days). In adjusted analysis, prior hospitalization (odds ratio [OR]: 2.01, 95% confidence interval [CI] 1.2-3.36), prior cephalosporin administration (OR 2.72, 95% CI: 1.54-4.83), and prior chemotherapy (OR: 3.26, 95% CI: 1.92-5.5) were significantly associated with CDI. CONCLUSIONS: Hospitalization, and prior antibiotic and chemotherapy use are risk factors that are not easily modifiable, which emphasizes the need to start investigating preventive or prophylactic strategies in this high-risk population.

Aging of the Liver: What This Means for Patients with HIV.

As the HIV population continues to live longer as a result of antiretroviral therapy, liver-related mortality has become one of the leading causes of non-AIDS related death in this patient population. The liver possesses a remarkable regenerative capacity but undergoes complex biological changes in response to aging and inflammation that result in decreased cellular regeneration and a tipping of the scales towards fibrogenesis. Patients with HIV infection have serological evidence of ongoing inflammation, with elevations in some biomarkers persisting despite adequate virologic control. In addition, HIV-co-infected patients have markers of advanced age on liver biopsy and increased prevalence of fibrosis as compared to an age-matched HCV mono-infected cohort. In this review, we will discuss the biology of aging, age-related changes in the liver, and the relevant mechanisms by which HIV causes inflammation in the context of accelerated aging, fibrosis of the liver, and other viral co-infection.

Intestinal microbiome disruption in patients in a long-term acute care hospital: A case for development of microbiome disruption indices to improve infection prevention.

BACKGROUND: Composition and diversity of intestinal microbial communities (microbiota) are generally accepted as a risk factor for poor outcomes; however, we cannot yet use this information to prevent adverse outcomes. METHODS: Stool was collected from 8 long-term acute care hospital patients experiencing diarrhea and 2 fecal microbiota transplant donors; 16S rDNA V1-V2 hypervariable regions were sequenced. Composition and diversity of each sample were described. Stool was also tested for Clostridium difficile, vancomycin-resistant enterococci (VRE), and carbapenem-resistant Enterobacteriaceae. Associations between microbiota diversity and demographic and clinical characteristics, including antibiotic use, were analyzed. RESULTS: Antibiotic exposure and Charlson Comorbidity Index were inversely correlated with diversity (Spearman = -0.7). Two patients were positive for VRE; both had microbiomes dominated by Enterococcus faecium, accounting for 67%-84% of their microbiome. CONCLUSIONS: Antibiotic exposure correlated with diversity; however, other environmental and host factors not easily obtainable in a clinical setting are also known to impact the microbiota. Therefore, direct measurement of microbiome disruption by sequencing, rather than reliance on surrogate markers, might be most predictive of adverse outcomes. If and when microbiome characterization becomes a standard diagnostic test, improving our understanding of microbiome dynamics will allow for interpretation of results to improve patient outcomes.

Characteristics and Antibiotic Use Associated With Short-Term Risk of Clostridium difficile Infection Among Hospitalized Patients.

OBJECTIVES: Polymerase chain reaction (PCR) has been shown to have an excellent sensitivity and specificity for the detection of Clostridium difficile infection (CDI). Little is known about risk factors for CDI within 14 days of an initial negative test. We sought to determine the characteristics among hospitalized patients associated with risk of short-term acquisition of CDI. METHODS: A case-control study was conducted. Cases were patients who converted from PCR negative to positive within 14 days. Each case was matched with three controls. Conditional logistic regression was used to estimate the association between patient characteristics and CDI. RESULTS: Of the 30 patients in our study who had a positive PCR within 14 days of a first negative PCR (cases), 15 (50%) occurred within 7 days of the initial test. Cases had a higher proportion of intravenous vancomycin use in the previous 8 weeks (odds ratio [OR], 3.38; 95% confidence interval [CI], 1.34-8.49) and were less likely to have recent antiviral agent use (OR, 0.30; 95% CI, 0.11-0.83) compared with controls. CONCLUSIONS: In hospitalized patients, treatment with intravenous vancomycin within the prior 8 weeks of a first negative PCR test for C difficile is a risk factor for short-term risk for hospital-acquired CDI. Repeat testing guidelines for C difficile PCR should take into consideration patients who may be at high risk for short-term acquisition of CDI.

Mycobacterium paraffinicum causing symptomatic pulmonary infection.

Mycobacterium paraffinicum has been newly recognized as a species. A case of symptomatic pulmonary infection caused by M. paraffinicum is described, and as far as we know, this is the first case of the organism as a human pathogen.

Pichia anomala (Candida pelliculosa) fungemia in a patient with sickle cell disease.

This case report discusses a patient with sickle cell disease who presented with fungemia from Pichia anomala (teleomorph: Candida pelliculosa). The organism was identified as P. anomala by MALDI-TOF VITEK mass spectrometry and VITEK 2 yeast identification card. Pichia anomala should be considered in sickle cell patients with recurrent fungemia.