Publications by authors named "Robert A Salata"

128 Publications

Dosing Colistimethate Every 8 h Results in Higher Plasma Concentrations of Active Colistin Than Every 12-Hourly Dosing without Increase in Nephrotoxicity: A Phase 1 Pharmacokinetics Trial in Healthy Adult Volunteers.

Antibiotics (Basel) 2022 Apr 6;11(4). Epub 2022 Apr 6.

Department of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA.

Despite its use for decades, pharmacokinetic (PK) and safety studies on colistin are limited. We conducted a phase l, open-label trial to evaluate the safety and PK of multiple doses of intravenous (IV) and aerosolized colistimethate sodium (CMS) administered separately and in combination. In total, 31 healthy adults were enrolled into three cohorts of 9, 10, and 12 participants, respectively. Each cohort received increasing doses of CMS over three dosing periods as follows: Period 1 (IV only), 2.5 mg/kg every 12 h (q12h) to 3.3 mg/kg every 8 h (q8h); Period 2 (aerosolized only), 75 mg 2-4 doses, and Period 3 (combined IV aerosolized), in which was Periods 1 and 2 combined. Safety assessments, serum and lung concentrations of colistin analytes (colistin A, colistin B, CMS A, and CMS B), and kidney biomarkers were measured at specified time points. Increasing the CMS dose from 2.5 mg/kg q12h to q8h resulted in a 33% increase in serum colistin A concentrations from 3.9 μg/mL to 5.3 μg/mL-well above the accepted target of 2 μg/mL for 6 h after dosing, without evidence of nephrotoxicity. However, there was an increase in neurotoxicity, primarily perioral and lingual paresthesias, and self-limited ataxia. IV administration did not increase the lung concentrations of colistin.
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http://dx.doi.org/10.3390/antibiotics11040490DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9029538PMC
April 2022

Carbapenem-Resistant Acinetobacter baumannii in U.S. Hospitals: Diversification of Circulating Lineages and Antimicrobial Resistance.

mBio 2022 04 21;13(2):e0275921. Epub 2022 Mar 21.

Division of Infectious Diseases, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.

Carbapenem-resistant Acinetobacter baumannii (CR) is a major cause of health care-associated infections. CR is typically multidrug resistant, and infection is difficult to treat. Despite the urgent threat that CR poses, few systematic studies of CR clinical and molecular epidemiology have been conducted. The Study Network of Acinetobacter as a Carbapenem-Resistant Pathogen (SNAP) is designed to investigate the clinical characteristics and contemporary population structure of CR circulating in U.S. hospital systems using whole-genome sequencing (WGS). Analysis of the initial 120 SNAP patients from four U.S. centers revealed that CR remains a significant threat to hospitalized patients, affecting the most vulnerable patients and resulting in 24% all-cause 30-day mortality. The majority of currently circulating isolates belonged to ST2, a part of clonal complex 2 (CC2), which is the dominant drug-resistant lineage in the United States and Europe. We identified three distinct sublineages within CC2, which differed in their antibiotic resistance phenotypes and geographic distribution. Most concerning, colistin resistance (38%) and cefiderocol resistance (10%) were common within CC2 sublineage C (CC2C), where the majority of isolates belonged to ST2/ST281. Additionally, we identified ST499 as the most common non-CC2 lineage in our study. Our findings suggest a shift within the CR population in the United States during the past 10 years and emphasize the importance of real-time surveillance and molecular epidemiology in studying CR dissemination and clinical impact. Carbapenem-resistant Acinetobacter baumannii (CR) constitutes a major threat to public health. To elucidate the molecular and clinical epidemiology of CR in the United States, clinical CR isolates were collected along with data on patient characteristics and outcomes, and bacterial isolates underwent whole-genome sequencing and antibiotic susceptibility phenotyping. Key findings included emergence of new sublineages within the globally predominant clonal complex 2 (CC2), increased colistin and cefiderocol resistance within one of the CC2 sublineages, and emergence of ST499 as the dominant non-CC2 CR lineage in U.S. hospitals.
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http://dx.doi.org/10.1128/mbio.02759-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9040734PMC
April 2022

Acceptability of the Dapivirine Vaginal Ring in Postmenopausal US Women.

AIDS Patient Care STDS 2022 Mar;36(3):97-105

Department of Medicine, Center for AIDS Prevention Studies, University of California, San Francisco, California, USA.

For women in the United States who remain sexually active beyond child-bearing years, susceptibility to HIV infection remains, yet condom use is low. We assessed acceptability of the dapivirine vaginal ring (ring) among 96 postmenopausal US women enrolled in a placebo-controlled multisite phase II trial of the ring, using questionnaires and in-depth interviews. Three quarters of women reported "perfect" adherence (ring never out) over the 3-month trial period. At study exit, the ring was found to be very easy to use by 72%, very comfortable to wear by 65%, and 4% reported it ever interfered with their daily activities. The most common worries among participants at preinitiation had decreased significantly at study exit (e.g., worries about inserting the ring declined from 46% to 6%, discomfort during daily activities from 53% to 3%, ring not staying in place from 48% to 14%, all  < 0.0001). Despite some couples feeling the ring during sex, the ring was perceived as more suitable than condoms for prevention because it was not burdensome to use, did not interfere with erection, and provided (for some) additional vaginal lubrication. The ring is a promising, highly acceptable HIV prevention method that is suitable to the lives of postmenopausal women and their male partners and can provide them with an additional prevention choice. Clinical Trials Registration: NCT02010593.
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http://dx.doi.org/10.1089/apc.2022.0002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8971982PMC
March 2022

Factors Associated with HBsAg Seropositivity among Pregnant Women Receiving Antenatal Care at 10 Community Health Centers in Freetown, Sierra Leone: A Cross-Sectional Study.

Pathogens 2022 Feb 12;11(2). Epub 2022 Feb 12.

Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.

Hepatitis B (HBV) is a major public health threat in Sierra Leone. Pregnant women are disproportionately impacted, yet little is known about the epidemiology of HBV in this group. We conducted a cross-sectional study of pregnant women aged ≥16 years receiving antenatal care across 10 community health centers in Freetown from July to September 2021 to assess the prevalence and associated factors of HBsAg seropositivity. Logistic regression was used to identify the predictors of HBsAg seropositivity. In total, 394 pregnant women were screened. The mean age was 24.4 ± 4.9 years, 78.2% were married, and 47.2% were in the second trimester. Only 1% had received the HBV vaccine. The prevalence of HBsAg was 7.9%, while HIV was 5.8% and HIV/HBV co-infection was 0.3%. Regarding high-risk practices, 76.6% reported female genital circumcision, 41.9% ear piercing, 29.0% endorsed multiple sexual partners, and 23.6% reported sexually transmitted infections. In the logistic regression analysis, having a husband/partner with HBV (adjusted odds ratio (aOR): 6.54; 95% CI: [1.72-24.86]; = 0.006) and residing in Central Freetown (aOR: 4.00; 95% CI: [1.46-11.00]; = 0.007) were independently associated with HBsAg seropositivity. Our findings support the scaling up of HBV services to target pregnant women and their partners for screening and vaccination to help reduce mother-to-child transmission rates in Sierra Leone.
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http://dx.doi.org/10.3390/pathogens11020243DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8874792PMC
February 2022

Characterizing HIV-1 Genetic Subtypes and Drug Resistance Mutations among Children, Adolescents and Pregnant Women in Sierra Leone.

Genes (Basel) 2021 08 26;12(9). Epub 2021 Aug 26.

Group of Virology and Pathogenesis, Galicia Sur Health Research Institute (IIS Galicia Sur), Complexo Hospitalario Universitario de Vigo, SERGAS-UVigo, 36213 Vigo, Spain.

Human immunodeficiency virus (HIV) drug resistance (HIVDR) is widespread in sub-Saharan Africa. Children and pregnant women are particularly vulnerable, and laboratory testing capacity remains limited. We, therefore, used a cross-sectional design and convenience sampling to characterize HIV subtypes and resistance-associated mutations (RAMs) in these groups in Sierra Leone. In total, 96 children (age 2-9 years, 100% ART-experienced), 47 adolescents (age 10-18 years, 100% ART-experienced), and 54 pregnant women (>18 years, 72% ART-experienced) were enrolled. Median treatment durations were 36, 84, and 3 months, respectively, while the sequencing success rates were 45%, 70%, and 59%, respectively, among children, adolescents, and pregnant women. Overall, the predominant HIV-1 subtype was CRF02_AG (87.9%, 95/108), with minority variants constituting 12%. Among children and adolescents, the most common RAMs were M184V (76.6%, = 49/64), K103N (45.3%, = 29/64), Y181C/V/I (28.1%, = 18/64), T215F/Y (25.0%, = 16/64), and V108I (18.8%, = 12/64). Among pregnant women, the most frequent RAMs were K103N (20.6%, = 7/34), M184V (11.8%, = 4/34), Y181C/V/I (5.9%, = 2/34), P225H (8.8%, = 3/34), and K219N/E/Q/R (5.9%, = 2/34). Protease and integrase inhibitor-RAMs were relatively few or absent. Based on the genotype susceptibility score distributions, 73%, 88%, and 14% of children, adolescents, and pregnant women, respectively, were not susceptible to all three drug components of the WHO preferred first-line regimens per 2018 guidelines. These findings suggest that routine HIVDR surveillance and access to better ART choices may improve treatment outcomes in Sierra Leone.
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http://dx.doi.org/10.3390/genes12091314DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8469552PMC
August 2021

Impact of COVID-19 on Tuberculosis Case Detection and Treatment Outcomes in Sierra Leone.

Trop Med Infect Dis 2021 Aug 19;6(3). Epub 2021 Aug 19.

Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.

The COVID-19 pandemic has adversely affected tuberculosis (TB) care delivery in high burden countries. We therefore conducted a retrospective study to assess the impact of COVID-19 on TB case detection and treatment outcomes at the Chest Clinic at Connaught Hospital in Freetown, Sierra Leone. Overall, 2300 presumptive cases were tested during the first three quarters of 2020 (intra-COVID-19) versus 2636 in 2019 (baseline), representing a 12.7% decline. Testing declined by 25% in women, 20% in children and 81% in community-initiated referrals. Notwithstanding, laboratory-confirmed TB cases increased by 37.0% and treatment success rate was higher in 2020 (55.6% vs. 46.7%, = 0.002). Multivariate logistic regression analysis found that age < 55 years (aOR 1.74, 95% CI (1.80, 2.56); = 0.005), new diagnosis (aOR 1.69, 95% CI (1.16, 2.47); = 0.007), pulmonary TB (aOR 3.17, 95% CI (1.67, 6.04); < 0.001), HIV negative status (aOR 1.60, 95%CI (1.24, 2.06); < 0.001) and self-administration of anti-TB drugs through monthly dispensing versus directly observed therapy (DOT) (aOR 1.56, 95% CI (1.21, 2.03); = 0.001) independently predicted treatment success. These findings may have policy implications for DOTS in this setting and suggest that more resources are needed to reverse the negative impact of the COVID-19 pandemic on TB program activities in Sierra Leone.
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http://dx.doi.org/10.3390/tropicalmed6030154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8396336PMC
August 2021

Assessing eligibility for differentiated service delivery, HIV services utilization and virologic outcomes of adult HIV-infected patients in Sierra Leone: a pre-implementation analysis.

Glob Health Action 2021 01;14(1):1947566

Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.

Background: There are limited data to help guide implementation of differentiated HIV service delivery (DSD) in resource-limited settings in sub-Saharan Africa.

Objectives: This pre-implementation study sought to assess the proportion of patients eligible for DSD and HIV services utilization, as well as risk factor analysis of virologic failure in Sierra Leone.

Methods: We conducted a retrospective study of adult HIV-infected patients aged 18 years and older receiving care at the largest HIV treatment center in Sierra Leone 2019-2020. Multiple logistic regression was used to identify predictors of virologic failure.

Results: Of 586 unique patients reviewed, 210 (35.8%) qualified as 'stable' for antiretroviral therapy (ART) delivery. There was high utilization of certain HIV service programs (e.g. HIV status disclosure to partners (83%) and treatment 'buddy' program participation (62.8%)), while other service programs (e.g. partner testing and community HIV support group participation) had low utilization (<50%). Of 429 patients with available viral load, 277 (64.6%) were virologically suppressed. In the multivariate logistic regression analysis of risk factors of virologic failure, CD4 < 350 cells/mm (p = 0.009), atazanavir-based ART (p = 0.032), once monthly versus once two- or three-monthly ART dispensing (p = 0.028), history of ART switching (p = 0.02), poor adherence (p = 0.001) and not having received adherence support (p < 0.001) were independent predictors of virologic failure.

Conclusion: Approximately one in three HIV-infected patients on ART were eligible for DSD. We identified gaps in HIV care (i.e. low partner testing, treatment 'buddy', program participation and a substantially high rate of virologic failure) that need to be addressed in preparation for full implementation of DSD in Sierra Leone.
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http://dx.doi.org/10.1080/16549716.2021.1947566DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8381912PMC
January 2021

Glycan Nanostructures of Human Coronaviruses.

Int J Nanomedicine 2021 15;16:4813-4830. Epub 2021 Jul 15.

Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH, USA.

Human coronaviruses present a substantial global disease burden, causing damage to populations' health, economy, and social well-being. Glycans are one of the main structural components of all microbes and organismic structures, including viruses-playing multiple essential roles in virus infection and immunity. Studying and understanding virus glycans at the nanoscale provide new insights into the diagnosis and treatment of viruses. Glycan nanostructures are considered potential targets for molecular diagnosis, antiviral therapeutics, and the development of vaccines. This review article describes glycan nanostructures (eg, glycoproteins and glycolipids) that exist in cells, subcellular structures, and microbes. We detail the structure, characterization, synthesis, and functions of virus glycans. Furthermore, we describe the glycan nanostructures of different human coronaviruses, such as human coronavirus 229E (HCoV-229E), human coronavirus OC43 (HCoV-OC43), severe acute respiratory syndrome-associated coronavirus (SARS-CoV), human coronavirus NL63 (HCoV-NL63), human coronavirus HKU1 (HCoV-HKU1), the Middle East respiratory syndrome-associated coronavirus (MERS-CoV), and how glycan nanotechnology can be useful to prevent and combat human coronaviruses infections, along with possibilities that are not yet explored.
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http://dx.doi.org/10.2147/IJN.S302516DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8289332PMC
September 2021

Brief Report: Herpes Simplex Virus Type-2 Shedding and Genital Ulcers During Early HIV in Zimbabwean Women.

J Acquir Immune Defic Syndr 2021 06;87(2):789-793

Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, MD.

Background: Herpes simplex virus type-2 (HSV-2) seropositive persons have a 3- to 5-fold higher risk of acquiring HIV, possibly because of HSV-2-induced inflammation and recruitment of susceptible immune cells to exposure sites. We hypothesized that cervical HSV-2 activation (ie, viral DNA shedding and/or ulcers) preceded HIV acquisition in the hormonal contraception and HIV cohort.

Methods: Zimbabwean women who acquired HIV were matched to HIV-negative women on visit, age, and bacterial sexually transmitted infections. Up to 5 cervical swabs bracketing first polymerase chain reaction detection of HIV DNA (the index visit) were selected (t-6months, t-3months, tindex, t+3months, t+6months). Women with HSV-2 immunoglobulin G+ before tindex were polymerase chain reaction tested for viral shedding. Self-reported and clinician-diagnosed ulcers were documented. Multivariable logistic regression, accounting for matching, estimated adjusted odds ratios (aOR) and 95% confidence intervals (CIs) at each visit.

Results: Of 387 HSV-2 seropositive women, most had prevalent as compared with incident HSV-2 (91% vs. 9%, respectively). HSV-2 viral shedding was more common among HIV seroconverters than HIV-negative women (26% vs. 14%, P < 0.01). Shedding occurred around HIV acquisition (t-3months aOR, 2.7; 95% CI, 0.8 to 8.8; tindex aOR, 2.6; 95% CI, 1.1 to 6.5; t+3months aOR, 2.6; 95% CI, 1.0 to 6.6). Genital ulcers were reported more often among HIV seroconverters than HIV-negative women (13% vs. 7%; P = 0.06) and detection was after HIV acquisition (t+6months aOR, 14.5; 95% CI, 1.6 to 133.9).

Conclusions: HSV-2 shedding appeared synergistic with HIV acquisition followed by presentation of ulcers. Evaluating all sexually transmitted infections rather than HSV-2 alone may clarify the relationship between inflammation and HIV acquisition.
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http://dx.doi.org/10.1097/QAI.0000000000002641DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8131209PMC
June 2021

Pharmacokinetic and Pharmacodynamic Profiling of Minocycline for Injection following a Single Infusion in Critically Ill Adults in a Phase IV Open-Label Multicenter Study (ACUMIN).

Antimicrob Agents Chemother 2021 02 17;65(3). Epub 2021 Feb 17.

Northwestern University, Chicago, Illinois, USA.

Intravenous (i.v.) minocycline is increasingly used to treat infections caused by multidrug-resistant (MDR) Despite its being approved nearly 50 years ago, published information on its pharmacokinetic (PK) profile is limited. This multicenter study examined the PK and probability of pharmacokinetic-pharmacodynamic (PK-PD) target attainment profile of i.v. minocycline in critically ill patients, with suspected or documented infection with Gram-negative bacteria. The PK study population included 55 patients who received a single 200-mg i.v. dose of minocycline. Plasma PK samples were collected predose and 1, 4, 12, 24, 36, and 48 h after initiation of minocycline. Total and unbound minocycline concentrations were determined at each time point. Probabilities of achieving the PK-PD targets associated with stasis and 1-log killing (free area under the curve above the MIC [AUC:MIC] of 12 and 18, respectively) in an immunocompetent animal pneumonia infection model of were evaluated. A two-compartment population PK model with zero-order i.v. input and first-order elimination, which estimated a constant fraction unbound (f) for minocycline, best characterized the total and unbound plasma minocycline concentration-time data. The only two covariates retained in the final PK model were body surface area (associated with central volume of distribution) and albumin (associated with f). In the PK-PD probability of target attainment analyses, minocycline 200 mg i.v. every 12 h (Q12H) was predicted to result in a suboptimal PK-PD profile for patients with infections with MIC values of >1 mg/liter. Like all PK-PD profiling studies of this nature, these findings need clinical confirmation.
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http://dx.doi.org/10.1128/AAC.01809-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8092545PMC
February 2021

Prevalence of hepatitis B surface antigen and serological markers of other endemic infections in HIV-infected children, adolescents and pregnant women in Sierra Leone: A cross-sectional study.

Int J Infect Dis 2021 Jan 28;102:45-52. Epub 2020 Sep 28.

Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH, USA; Division of Infectious Diseases and HIV Medicine, University Hospitals Cleveland Medical Center, Cleveland, OH, USA.

Objective: To assess the prevalence of serological markers of HBV and endemic acute and chronic infections (HAV, HCV, CMV, HTLV-1/2 and syphilis) in HIV-infected children, adolescents and pregnant women in Sierra Leone.

Method: We conducted a cross-sectional study at the national children's and women's hospitals in Freetown. Logistic regression was used to assess predictors of HBsAg positivity.

Results: 183 HIV-infected participants were enrolled, comprising children (n = 88), adolescents (n = 47) and pregnant women (n = 48). All participants (100%) were CMV IgG-positive, while 56.8%, 93.6% and 100% of children, adolescents and pregnant women, respectively, were HAV IgG-positive. The prevalence of HCV, HTLV-1/2 and syphilis were <4%. HBV markers were distributed as follows-children: HBsAg (2.3%), HBeAg (0%), anti-HBc (5.7%); adolescents: HBsAg (17.0%), HBeAg (6.4%), anti-HBc (27.7%); and pregnant women: HBsAg (18.8%), HBeAg (4.2%), anti-HBc (77.1%). Age >10 years, i.e., being born pre-2009 before implementation of routine hepatitis B immunization (aOR 5.05 [1.18-21.28]; p = 0.029) and CD4 count <350 cells/mm (aOR 3.97 [1.07-14.71]; p = 0.039) predicted HBsAg positivity.

Conclusion: A high burden of chronic HBV and other endemic infections was observed among HIV-infected patients born pre-2009 before implementation of routine HBV immunization in Sierra Leone, warranting targeted screening and immunization of this high-risk population.
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http://dx.doi.org/10.1016/j.ijid.2020.09.1459DOI Listing
January 2021

SARS-CoV-2 infection in a patient on chronic hydroxychloroquine therapy: Implications for prophylaxis.

IDCases 2020 27;20:e00778. Epub 2020 Apr 27.

Division of Infectious Diseases and HIV Medicine, University Hospitals Cleveland Medical Center, Case Western Reserve University, Cleveland, OH, USA.

People exposed to COVID-19 have a risk of developing disease, and health care workers are at risk at a time when they are badly needed during a health care crisis. Hydroxychloroquine and chloroquine have been used as treatment and are being considered as prophylaxis. Our patient developed COVID-19 while on hydroxychloroquine and although more work is needed, this calls into question the role of these medications as preventive therapy.
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http://dx.doi.org/10.1016/j.idcr.2020.e00778DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7185003PMC
April 2020

Diagnosis and treatment outcomes of adult tuberculosis in an urban setting with high HIV prevalence in Sierra Leone: A retrospective study.

Int J Infect Dis 2020 Jul 24;96:112-118. Epub 2020 Apr 24.

Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA; Division of Infectious Diseases and HIV Medicine, University Hospitals Cleveland Medical Center, Cleveland, Ohio, USA; Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.

Objective: To assess the diagnosis, treatment outcomes, and predictors of mortality in adult tuberculosis (TB) patients in an urban setting with a high HIV prevalence.

Methods: A retrospective study was conducted of adult TB patients aged ≥15 years who were treated at Connaught Hospital in Freetown, Sierra Leone from January through December 2017. Multivariate logistic regression was used to identify predictors of mortality.

Results: Of 1127 TB cases notified in 2017, 1105 (98%) were tested for HIV, yielding a TB/HIV co-infection rate of 32.0%. Only HIV-tested cases (n=1105) were included in the final analysis. The majority were male (69.3%), aged 25-34 years (29.2%), and had pulmonary TB (96.3%). Treatment outcomes were as follows: 29.0% cured, 29.0% completed, 0.5% treatment failure, 24.2% lost to follow-up, 12.8% transferred/not evaluated, and 4.5% died. The majority of deaths (80.0%, 40/50) occurred within 2 months of TB treatment initiation. Age 65 years or older (adjusted odds ratio 3.48, 95% confidence interval 1.15-10.56; p=0.027) and HIV-positive status (adjusted odds ratio 3.50, 95% confidence interval 1.72-7.12; p=0.001) were independent predictors of mortality.

Conclusions: Suboptimal TB treatment outcomes were observed in Sierra Leone in 2017. More local and international action is warranted to help achieve the 2035 global TB elimination targets.
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http://dx.doi.org/10.1016/j.ijid.2020.04.038DOI Listing
July 2020

A Phase 3 Study to Compare Delafloxacin With Moxifloxacin for the Treatment of Adults With Community-Acquired Bacterial Pneumonia (DEFINE-CABP).

Open Forum Infect Dis 2020 Jan 5;7(1):ofz514. Epub 2019 Dec 5.

Melinta Therapeutics, Lincolnshire, Illinois, USA.

Background: The clinical and economic burden of community-acquired bacterial pneumonia (CABP) is significant and is anticipated to increase as the population ages and pathogens become more resistant. Delafloxacin is a fluoroquinolone antibiotic approved in the United States for the treatment of adults with acute bacterial skin and skin structure infections. Delafloxacin's shape and charge profile uniquely impact its spectrum of activity and side effect profile. This phase 3 study compared the efficacy and safety of delafloxacin with moxifloxacin for the treatment of CABP.

Methods: A randomized, double-blind, comparator-controlled, multicenter, global phase 3 study compared the efficacy and safety of delafloxacin 300 mg twice daily or moxifloxacin 400 mg once daily in adults with CABP. The primary end point was early clinical response (ECR), defined as improvement at 96 (±24) hours after the first dose of study drug. Clinical response at test of cure (TOC) and microbiologic response were also assessed.

Results: In the intent-to-treat analysis population (ITT), ECR rates were 88.9% in the delafloxacin group and 89.0% in the moxifloxacin group. Noninferiority of delafloxacin compared with moxifloxacin was demonstrated. At TOC in the ITT population, the success rates were similar between groups. Treatment-emergent adverse events that were considered at least possibly related to the study drug occurred in 65 subjects (15.2%) in the delafloxacin group and 54 (12.6%) in the moxifloxacin group.

Conclusions: Intravenous/oral delafloxacin monotherapy is effective and well tolerated in the treatment of adults with CABP, providing coverage for Gram-positive, Gram-negative, and atypical pathogens.

Clinicaltrialsgov Identifier: NCT03534622.
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http://dx.doi.org/10.1093/ofid/ofz514DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6975251PMC
January 2020

Aberrant cervical innate immunity predicts onset of dysbiosis and sexually transmitted infections in women of reproductive age.

PLoS One 2020 8;15(1):e0224359. Epub 2020 Jan 8.

CONRAD, Arlington, VA, United States of America.

Sexually transmitted infections (STIs) and vaginal dysbiosis (disturbed resident microbiota presenting with abnormal Nugent score or candidiasis) have been associated with mucosal inflammation and risk of HIV-1 infection, cancer and poor reproductive outcomes. To date, the temporal relationships between aberrant cervical innate immunity and the clinical onset of microbial disturbance have not been studied in a large population of reproductive age women. We examined data from a longitudinal cohort of 934 Ugandan and Zimbabwean women contributing 3,274 HIV-negative visits who had complete laboratory, clinical and demographic data. Among those, 207 women later acquired HIV, and 584 women were intermittently diagnosed with C. trachomatis (CT), N. gonorrhoeae (NG), genital herpes (HSV-2), T. vaginalis (TV), candidiasis, and abnormal intermediate (4-6) or high (7-10) Nugent score, i.e. bacterial vaginosis (BV). Immune biomarker concentrations in cervical swabs were analyzed by generalized linear and mixed effect models adjusting for site, age, hormonal contraceptive use (HC), pregnancy, breastfeeding, genital practices, unprotected sex and overlapping infections. High likelihood ratios (1.5-4.9) denoted the values of cervical immune biomarkers to predict onset of abnormal Nugent score and candidiasis at the next visits. When controlling for covariates, higher levels of β-defensin-2 were antecedent to BV, CT and HSV-2, lower anti-inflammatory ratio IL-1RA:IL-1β-to intermediate Nugent scores and candida, lower levels of the serine protease inhibitor SLPI-to candida, lower levels of the adhesion molecule ICAM-1 -to TV, and lower levels of the oxidative stress mitigator and endothelial activation marker VEGF-to NG. Changes in innate immunity following onset of dysbiosis and infections were dependent on HC use when controlling for all other covariates. In conclusion, imminent female genital tract dysbiosis or infection can be predicted by distinct patterns of innate immunity. Future research should characterize biotic and abiotic determinants of this pre-existing innate immunity state.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0224359PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6948729PMC
March 2020

Causes of hospitalization and predictors of HIV-associated mortality at the main referral hospital in Sierra Leone: a prospective study.

BMC Public Health 2019 Oct 21;19(1):1320. Epub 2019 Oct 21.

Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH, USA.

Background: HIV infection is a growing public health problem in Sierra Leone and the wider West Africa region. The countrywide HIV prevalence was estimated at 1.7% (67,000 people), with less than 30% receiving life-saving ART in 2016. Thus, HIV-infected patients tend to present to health facilities late, with high mortality risk.

Methods: We conducted a prospective study of HIV inpatients aged ≥15 years at Connaught Hospital in Freetown-the main referral hospital in Sierra Leone-from July through September 2017, to assess associated factors and predictors of HIV-related mortality.

Results: One hundred seventy-three HIV inpatients were included, accounting for 14.2% (173/1221) of all hospital admissions during the study period. The majority were female (59.5%, 70/173), median age was 34 years, with 51.4% (89/173) of them diagnosed with HIV infection for the first time during the current hospitalization. The most common admitting diagnoses were anemia (48%, 84/173), tuberculosis (24.3%, 42/173), pneumonia (17.3%, 30/173) and diarrheal illness (15.0%, 26/173). CD4 count was obtained in 64.7% (112/173) of patients, with median value of 87 cells/μL (IQR 25-266), and was further staged as severe immunosuppression: CD4 < 100 cells/μL (50%, 56/112); AIDS: CD4 < 200 cells/μL (69.6%, 78/112); and late-stage HIV disease: CD4 < 350 cells/μL (83%, 93/112). Fifty-two patients (30.1%, 52/173) died during hospitalization, 23% (12/52) of them within the first week. The leading causes of death were anemia (23.1%, 12/52), pneumonia (19.2%, 10/52), diarrheal illness (15.4%, 8/52) and tuberculosis (13.6%, 7/52). Neurological symptoms, i.e., loss of consciousness (p = 0.04) and focal limb weakness (p = 0.04); alcohol use (p = 0.01); jaundice (p = 0.02); cerebral toxoplasmosis (p = 0.01); and tuberculosis (p = 0.04) were significantly associated with mortality; however, only jaundice (AOR 0.11, 95% CI [0.02-0.65]; p = 0.01) emerged as an independent predictor of mortality.

Conclusion: HIV-infected patients account for a substantial proportion of admissions at Connaught Hospital, with a high morbidity and in-hospital mortality burden. These findings necessitate the implementation of specific measures to enhance early HIV diagnosis and expand treatment access to all HIV-infected patients in Sierra Leone.
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http://dx.doi.org/10.1186/s12889-019-7614-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6805411PMC
October 2019

A two-part phase 1 study to establish and compare the safety and local tolerability of two nasal formulations of XF-73 for decolonisation of Staphylococcus aureus: A previously investigated 0.5mg/g viscosified gel formulation versus a modified formulation.

J Glob Antimicrob Resist 2020 06 7;21:171-180. Epub 2019 Oct 7.

Department of Medicine and Division of Infectious Diseases and HIV Medicine, University Hospitals Cleveland Medical Center, Case Western Reserve University, Cleveland, OH, USA.

Objectives: Successful decolonisation of nasal Staphylococcus aureus (SA) carriage by mupirocin is limited by increasing drug resistance. This randomised, open-label, phase 1 study compared the safety and local tolerability of two nasal formulations of XF-73, a novel porphyrinic antibacterial with rapid intrinsic activity against SA.

Methods: The study was performed in 60 healthy adults. In Part 1, eight non-SA carriers were randomised to groups of four subjects each and were treated with XF-73 concentrations of 0.5mg/g 2% gel or 2.0mg/g 2% gel. In Part 2, 52 persistent SA carriers were randomised to groups of 13 subjects each and were treated with XF-73 concentrations of 0.5mg/g 2% gel, 2.0mg/g 2% gel, 0.5mg/g 4% gel or 4% viscosified placebo gel. Plasma pharmacokinetic and pharmacodynamic studies were performed. Antistaphylococcal activity was assessed as the presence/absence of SA and by quantification of colonisation using a semiquantitative scale (SA score).

Results: 56 subjects (8/8 from Part 1 and 48/52 from Part 2) completed the study, with 47/60 comprising the pharmacokinetic population and 48/60 the pharmacodynamic population. There was no measurable systemic absorption of XF-73. XF-73 treatment was associated with rapid reduction in SA score in all subjects. The most common treatment-emergent adverse events (TEAEs) were rhinorrhoea and nasal dryness (15.5% each in Parts 1 and 2). TEAEs were mild and resolved spontaneously.

Conclusion: XF-73 was well tolerated with minimal side effects at doses of 0.5mg/g 2% gel and 2.0mg/g 2% gel. These findings support further development of XF-73.
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http://dx.doi.org/10.1016/j.jgar.2019.09.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7136135PMC
June 2020

Development and validation of an LC-MS/MS method for the simultaneous determination of bedaquiline and rifabutin in human plasma.

J Pharm Biomed Anal 2019 Nov 16;176:112775. Epub 2019 Aug 16.

The University of Toledo, Department of Pediatrics, 3000 Arlington Ave., Toledo, OH 43614, USA; Professor The University of Toledo, Department of Pediatrics, Toledo, OH, USA.

This article describes the simultaneous determination of bedaquiline fumarate (TMC-207) and rifabutin in human plasma by stable isotope dilution tandem mass spectrometry. The methodology was developed for an investigation of potential drug-drug interactions of the two anti-tuberculosis drugs when given together to healthy human volunteers. Use of the two drugs in combination to treat disease caused by Mycobacterium tuberculosis is contemplated as the bacterium becomes resistant to many currently available drugs.
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http://dx.doi.org/10.1016/j.jpba.2019.07.023DOI Listing
November 2019

The Pitt Bacteremia Score Predicts Mortality in Nonbacteremic Infections.

Clin Infect Dis 2020 04;70(9):1826-1833

Division of Infectious Diseases, University of North Carolina, Chapel Hill.

Background: Predicting mortality risk in patients is important in research settings. The Pitt bacteremia score (PBS) is commonly used as a predictor of early mortality risk in patients with bloodstream infections (BSIs). We determined whether the PBS predicts 14-day inpatient mortality in nonbacteremia carbapenem-resistant Enterobacteriaceae (CRE) infections.

Methods: Patients were selected from the Consortium on Resistance Against Carbapenems in Klebsiella and Other Enterobacteriaceae, a prospective, multicenter, observational study. We estimated risk ratios to analyze the predictive ability of the PBS overall and each of its components individually. We analyzed each component of the PBS in the prediction of mortality, assessed the appropriate cutoff value for the dichotomized score, and compared the predictive ability of the qPitt score to that of the PBS.

Results: In a cohort of 475 patients with CRE infections, a PBS ≥4 was associated with mortality in patients with nonbacteremia infections (risk ratio [RR], 21.9; 95% confidence interval [CI], 7.0, 68.8) and with BSIs (RR, 6.0; 95% CI, 2.5, 14.4). In multivariable analysis, the hypotension, mechanical ventilation, mental status, and cardiac arrest parameters of the PBS were independent risk factors for 14-day all-cause inpatient mortality. The temperature parameter as originally calculated for the PBS was not independently associated with mortality. However, a temperature <36.0°C vs ≥36°C was independently associated with mortality. A qPitt score ≥2 had similar discrimination as a PBS ≥4 in nonbacteremia infections.

Conclusions: Here, we validated that the PBS and qPitt score can be used as reliable predictors of mortality in nonbacteremia CRE infections.
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http://dx.doi.org/10.1093/cid/ciz528DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7156778PMC
April 2020

Prevalence of drug resistance mutations among ART-naive and -experienced HIV-infected patients in Sierra Leone.

J Antimicrob Chemother 2019 07;74(7):2024-2029

Group of Virology and Pathogenesis, Galicia Sur Health Research Institute (IIS Galicia Sur)-Complexo Hospitalario Universitario de Vigo, SERGAS-UVigo, Vigo, Spain.

Objectives: The aim of this study was to assess the prevalence of HIV drug resistance (HIVDR) in HIV-infected ART-naive and -experienced patients in Sierra Leone.

Patients And Methods: We conducted a cross-sectional study of HIV-positive adults aged ≥18 years at Connaught Hospital in Freetown, Sierra Leone in November 2017. Sequencing was performed in the reverse transcriptase, protease and integrase regions, and interpreted using the Stanford HIVDR database and WHO 2009 mutation list.

Results: Two hundred and fifteen HIV-infected patients were included (64 ART naive and 151 ART experienced). The majority (66%) were female, the median age was 36 years and the median ART exposure was 48 months. The majority (83%) were infected with HIV-1 subtype CRF02_AG. In the ART-naive group, the pretreatment drug resistance (PDR) prevalence was 36.7% (14.2% to NRTIs and 22.4% to NNRTIs). The most prevalent PDR mutations were K103N (14.3%), M184V (8.2%) and Y181C (4.1%). In the ART-experienced group, 64.4% harboured resistance-associated mutations (RAMs) and the overall prevalence of RAMs to NRTIs and NNRTIs was 85.2% (52/61) and 96.7% (59/61), respectively. The most prevalent RAMs were K103N (40.7%), M184V (28.8%), D67N (15.3%) and T215I/F/Y (15.3%). Based on the genotypic susceptibility score estimates, 22.4% of ART-naive patients and 56% of ART-experienced patients were not susceptible to first-line ART used in Sierra Leone.

Conclusions: A high prevalence of circulating NRTI- and NNRTI-resistant variants was observed in ART-naive and -experienced HIV-1-infected patients in Sierra Leone. This necessitates the implementation of HIVDR surveillance programmes to inform national ART guidelines for the treatment and monitoring of HIV-infected patients in Sierra Leone.
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http://dx.doi.org/10.1093/jac/dkz134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6587425PMC
July 2019

Seroprevalence of Hepatitis B, Hepatitis C, and Human T-Cell Lymphotropic Virus Infections in HIV-Infected Patients in Sierra Leone.

Am J Trop Med Hyg 2019 06;100(6):1521-1524

Division of Infectious Diseases and HIV Medicine, University Hospitals Cleveland Medical Center, Cleveland, Ohio.

HIV coinfection with hepatitis B virus (HBV), hepatitis C virus (HCV), and human T-cell lymphotropic viruses 1 and 2 (HTLV-1 and HTLV-2) is common because of shared transmission routes. There is no published data on the prevalence of these infections in people living with HIV in Sierra Leone. We conducted a cross-sectional study of 211 HIV-positive patients aged ≥ 18 years in Freetown, Sierra Leone, in November 2017. Plasma samples were analyzed using the chemiluminescent microparticle immunoassay (Architect System, Abbott ARCHITECT Analyzer, Abbott Park, IL. The majority were female (63.5%), with median age 36 years (interquartile range [IQR]: 32-44) and median CD4 count of 396 cells/µL (IQR: 214-534). Sixty patients (28.4%) were newly diagnosed and antiretroviral therapy (ART) naive; 151 patients (71.6%) were ART experienced. The prevalence of the hepatitis B surface antigen (HBsAg), total anti-hepatitis B core antibody, and anti-HCV was 21.7%, 82.9%, and 4.3%, respectively. No cases of HTLV-1 or HTLV-2 were detected. Male gender ( = 0.004) and CD4 < 350 cells/µL ( = 0.017) were associated with the HBsAg positive status.
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http://dx.doi.org/10.4269/ajtmh.18-1001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6553887PMC
June 2019

The Effect of an HIV Self-Management Intervention on Neurocognitive Behavioral Processing.

West J Nurs Res 2019 07 17;41(7):990-1008. Epub 2019 Jan 17.

1 Frances Payne Bolton School of Nursing, Case Western Reserve University, Cleveland, OH, USA.

People living with HIV (PLHIV) are increasingly diagnosed with comorbidities which require increasing self-management. We examined the effect of a self-management intervention on neurocognitive behavioral processing. Twenty-nine PLHIV completed a two-group, 3-month randomized clinical trial testing a self-management intervention to improve physical activity and dietary intake. At baseline and 3 months later, everyone completed validated assessments of physical, diet, and neurocognitive processing (functional magnetic resonance imaging [fMRI]-derived network analyses). We used linear mixed effects modeling with a random intercept to examine the effect of the intervention. The intervention improved healthy eating ( = .08) but did not improve other self-management behaviors. There was a significant effect of the intervention on several aspects of neurocognitive processing including in the task positive network (TPN) differentiation ( = .047) and an increase in the default mode network (DMN) differentiation ( = .10). Self-management interventions may influence neurocognitive processing in PLHIV, but those changes were not associated with positive changes in self-management behavior.
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http://dx.doi.org/10.1177/0193945918823347DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6570548PMC
July 2019

The Role of Trimethoprim/Sulfamethoxazole in the Treatment of Infections Caused by Carbapenem-Resistant .

Open Forum Infect Dis 2019 Jan 14;6(1):ofy351. Epub 2018 Dec 14.

Institute for Global Health and Infectious Diseases, University of North Carolina, Chapel Hill, North Carolina.

In the Consortium on Resistance Against Carbapenems in and other (CRACKLE), trimethoprim-sulfamethoxazole (TMP-SMX) had a limited role in the treatment of less severe carbapenem-resistant (CRE) infections, especially urinary tract infections. Of tested CRE, only 29% were susceptible to TMP-SMX. Development of resistance further limits the use of TMP-SMX in CRE infections.
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http://dx.doi.org/10.1093/ofid/ofy351DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6324543PMC
January 2019

Effects of Rifamycin Coadministration on Bedaquiline Desmethylation in Healthy Adult Volunteers.

Clin Pharmacol Drug Dev 2019 05 30;8(4):436-442. Epub 2018 Nov 30.

Department of Pediatrics, University of Toledo College of Medicine, Toledo, OH, USA.

There is an urgent need to identify safe and effective combination treatments for multidrug-resistant (MDR) Mycobacterium tuberculosis infection (TB). Bedaquiline, a new diarylquinoline, is approved for the treatment of MDR pulmonary TB in combination with other drugs, which could include rifabutin, which is also used to treat drug-resistant TB. Both rifabutin and bedaquiline are metabolized via cytochrome P450 3A4, and rifabutin is an inducer of this enzyme. Bedaquiline is metabolized into its primary N-monodesmethyl metabolite, M2, and further desmethylated into an N-didesmethyl metabolite, M3. Both metabolites are cytotoxic and induce phospholipidosis. The effect of rifabutin on the generation and disposition of the 2 metabolites was investigated in healthy adult volunteers coadministered bedaquiline and either rifabutin or rifampin. Subjects received single oral doses (400 mg) of bedaquiline on days 1 and 29. Oral rifabutin (300 mg) or rifampin (600 mg) were given daily on days 20-41. In the rifabutin group maximum M2 concentrations (C ) increased significantly (P < .001) from 47.59 to 79.53 ng/mL, and clearance slowed slightly (P = .01). This resulted in significantly (P < .001) increased overall exposure (area under the concentration-time curve [AUC ]). Peak concentrations of M3 increased approximately 3-fold with little decline thereafter. In rifampin recipients M2 C doubled (48.44 to 101.52 ng/mL), but M2 clearance and time to C significantly (P < .001) increased, and AUC and mean residence time significantly decreased (P < .001). Peak M3 concentrations increased 4-fold and rapidly declined. Although both rifamycins accelerate desmethylation of bedaquiline and M2, differences in clearance resulted in sustained elevations of both metabolites during rifabutin, but not rifampin, treatment.
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http://dx.doi.org/10.1002/cpdd.639DOI Listing
May 2019

Phase 2a Safety, Pharmacokinetics, and Acceptability of Dapivirine Vaginal Rings in US Postmenopausal Women.

Clin Infect Dis 2019 03;68(7):1144-1151

Division of Clinical Pharmacology, Department of Medicine, Johns Hopkins University, Baltimore, Maryland.

Background: Postmenopausal women have unique sociobiological human immunodeficiency virus (HIV) risks. We evaluated the safety, pharmacokinetics, and acceptability of a microbicide dapivirine (DPV) vaginal ring (VR) versus placebo in postmenopausal women.

Methods: We enrolled 96 HIV-negative postmenopausal US women in a phase 2a double-blind, randomized (3:1) trial of monthly VRs containing 25 mg DPV or placebo used continuously for 12 weeks. We assessed safety by adverse events (AEs). DPV concentrations were quantified in plasma and vaginal fluid. Steady-state concentrations were analyzed at 4, 8, and 12 weeks using repeated measures ANOVA. We assessed acceptability by self-report.

Results: We found no differences in the proportion of women with related grade 2 or higher reproductive system AEs (DPV: 6/72 (8%), placebo: 3/24 (13%), P = .68) or grade 3 or higher AEs (DPV: 4/72 (6%), placebo: 0/24 (0%), P = .57). In the DPV arm, 2/72 (3%) declined to resume product use due to AEs. Median DPV concentrations in plasma (262.0 pg/mL at week 12) and vaginal fluid (40.6 ng/mg at week 12) were constant over 12 weeks and exceeded the in vitro 50% effective concentration by 5000-fold in vaginal fluid by week 4. VR acceptability was high; 84/93 (90%) "very much liked or liked" the VR.

Conclusions: DPV VRs were safe, well tolerated, and acceptable in postmenopausal women. Plasma concentrations were comparable to published data on DPV use in reproductive-age women (median plasma concentration: 264 pg/mL). Given the reassuring safety and pharmacokinetic data, the DPV VR is promising for preexposure prophylaxis in postmenopausal women.

Clinical Trials Registration: NCT02010593.
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http://dx.doi.org/10.1093/cid/ciy654DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6424088PMC
March 2019

High Prevalence of Late-Stage Disease in Newly Diagnosed Human Immunodeficiency Virus Patients in Sierra Leone.

Open Forum Infect Dis 2018 Sep 23;5(9):ofy208. Epub 2018 Aug 23.

Department of Medicine, Case Western Reserve University, Cleveland, Ohio.

A high prevalence of late-stage disease (75.4%) and severe immunosuppression (23.3%) was observed in 155 newly diagnosed human immunodeficiency virus patients in Freetown, Sierra Leone during August to November 2017. Within the late-stage diagnosis group, a significantly high proportion of patients reported fever (84.2% vs 65.2%; = .01), weight loss (82.2% vs 63.5%; = .01), and malaise (89.7% vs 71.7%; = .05). Fever was identified as the only independent predictor of late-stage disease in this study.
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http://dx.doi.org/10.1093/ofid/ofy208DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6121223PMC
September 2018

Renal infarction in vascular Ehlers-Danlos syndrome masquerading as pyelonephritis.

Clin Case Rep 2018 Aug 13;6(8):1478-1480. Epub 2018 Jun 13.

University Hospitals Cleveland Medical Center Case Western Reserve University Cleveland OH USA.

Symptoms associated with numerous diseases can be indistinguishable from those of the urinary system disorders because receptors of many visceral organs as well as the body wall transmit sensation through pain fibers shared with the kidneys. Disregarding important family background of genetic disorder can be detrimental for some patients.
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http://dx.doi.org/10.1002/ccr3.1639DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6099022PMC
August 2018

HIV/AIDS in Sierra Leone: Characterizing the Hidden Epidemic.

AIDS Rev 2018 Apr-Jun;20(2):104-113

Department of Medicine, Case Western Reserve University, Cleveland, Ohio, USA.

Sierra Leone is a low-income West African country that has dealt with waves of economic, political, and public health challenges in its recent past, including a decade-long brutal civil war and the Ebola epidemic of 2014-2016. The HIV/AIDS epidemic, which has raged on in the country since 1987, has long been characterized as stable. The latest UNAIDS report estimates a countrywide HIV prevalence rate of 1.7% in 2016 among adults aged 15-49 years. However, there are indications that the epidemic may be in fact escalating and unless arrested urgently, has the potential to deteriorate into a major public health emergency. Although there are high levels of HIV awareness among adults (over 94%), uptake in voluntary HIV testing has remained low (<30%), and under one-third (29%) of the country's 60,000 people living with HIV/AIDS were on antiretroviral therapy in 2015. This review attempts to address the paucity of scientific information on the subject by presenting the historical and epidemiological background to the HIV/AIDS epidemic in Sierra Leone. Other aspects of the HIV/AIDS epidemic in Sierra Leone are examined, including routine HIV screening and diagnosis, linkage to and retention in HIV care, clinical characteristics and molecular epidemiology, treatment coverage, and prevention strategies. Finally, we identify four key areas of challenge that are hampering current efforts attempting to bring the epidemic under control, and perspective is offered on the way forward.
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http://dx.doi.org/10.24875/AIDSRev.M18000022DOI Listing
October 2018

Mycobactericidal activity of bedaquiline plus rifabutin or rifampin in ex vivo whole blood cultures of healthy volunteers: A randomized controlled trial.

PLoS One 2018 2;13(5):e0196756. Epub 2018 May 2.

School of Medicine, Case Western Reserve University and University Hospitals Cleveland Medical Center, Cleveland, Ohio, United States of America.

Background: Bedaquiline, an antimycobacterial agent approved for drug-resistant tuberculosis, is metabolized by CYP3A4, an hepatic enzyme strongly induced by rifampin, an essential part of drug-sensitive tuberculosis treatment. We examined the pharmacokinetic interactions of bedaquiline plus either rifampin or rifabutin in 33 healthy volunteers. This sub-study of that trial examined the mycobactericidal activity of these drugs against intracellular Mycobacterium tuberculosis using ex vivo whole blood culture.

Methods: Subjects were randomly assigned to receive two single 400 mg doses of bedaquiline, alone, and, after a 4 week washout period, in combination with steady-state daily dosing of either rifabutin 300 mg or rifampin 600 mg. Blood samples were collected prior to dosing and at multiple time points subsequently, to measure plasma drug concentrations and bactericidal activity in ex vivo M tuberculosis-infected whole blood cultures (WBA).

Results: Single oral doses of bedaquiline produced readily detectable WBA ex vivo, reaching a maximal effect of -0.28 log/day, with negative values indicating bacterial killing. Plasma concentrations of 355 ng/ml were sufficient for intracellular mycobacteriostasis. Combined dosing with rifampin or rifabutin produced maximal effects of -0.91 and -0.79 log/d, respectively. However, the activity of the rifabutin combination was sustained throughout the dosing interval, thereby producing a greater cumulative or total effect. At low drug concentrations, rifabutin plus bedaquiline yielded greater mycobactericidal activity than the sum of their separate effects. Neither drug metabolites nor cellular drug accumulation could account for this observation.

Conclusions: The combination of rifabutin plus bedaquiline produces sustained intracellular mycobactericidal activity that is greater than the sum of their individual effects. Further studies of the treatment-shortening potential of this combination are warranted.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0196756PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5931679PMC
July 2018

A Human-Centered Approach to CV Care: Infrastructure Development in Uganda.

Glob Heart 2018 12 21;13(4):347-354. Epub 2018 Apr 21.

Division of Cardiovascular Medicine, University Hospitals Cleveland Medical Center, Cleveland, OH, USA; Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH, USA.

In this case study, we describe an ongoing approach to develop sustainable acute and chronic cardiovascular care infrastructure in Uganda that involves patient and provider participation. Leveraging strong infrastructure for HIV/AIDS care delivery, University Hospitals Harrington Heart and Vascular Institute and Case Western Reserve University have partnered with U.S. and Ugandan collaborators to improve cardiovascular capabilities. The collaboration has solicited innovative solutions from patients and providers focusing on education and advanced training, penicillin supply, diagnostic strategy (e.g., hand-held ultrasound), maternal health, and community awareness. Key outcomes of this approach have been the completion of formal training of the first interventional cardiologists and heart failure specialists in the country, establishment of 4 integrated regional centers of excellence in rheumatic heart disease care with a national rheumatic heart disease registry, a penicillin distribution and adherence support program focused on retention in care, access to imaging technology, and in-country capabilities to treat advanced rheumatic heart valve disease.
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http://dx.doi.org/10.1016/j.gheart.2018.02.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6258347PMC
December 2018
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