bluuebunny/crossref_metadata_2025 huggingface dataset:
High Tenofovir Failure Rates in an Emerging, Non-B Subtype HIV Epidemic
Authors: Salvana Edsel Maurice , Schwem Brian , Samonte Genesis , Telan Elizabeth , Tactacan-Abrenica Rosario , Ching Patrick , Mendoza Kevin , Arevalo Geraldine , Alejandria Marissa , Leyritana Katerina , Trinidad Lyka , Penalosa Christine , Lim Jodor
Published: October 2017

Background

The WHO-recommended regimen for antiretrovirals (ARVs) is tenofovir (TDF) + lamivudine/emtricitabine (3TC/FTC) + efavirenz (EFV), based on demonstrated superiority of TDF+FTC+EFV over zidovudine (AZT) +FTC+ EFV in clinical trials. However, there are reports of increasing TDF resistance in non-B subtypes. We have previously shown that HIV genotypes in the Philippines have shifted (https://idsa.confex.com/idsa/2014/webprogram/Paper45090.html) from B to CRF01_AE. We compared failure rates for ARVs during an acquired drug-resistance surveillance study.

Methods

We analyzed ARV data from a study with the Department of Health on treatment failure in Filipinos after one year of treatment. Institutional Board Review approval and informed consent were obtained.

Results

513 adult patients from 3 national treatment hubs (Philippine General Hospital, San Lazaro Hospital, Vicente Sotto Memorial Medical Center) were enrolled and analyzed. Treatment failure (viral load>1000 copies/mL) at one year for specific regimens are summarized in Table 1. No baseline genotyping was available. 53 (10.3%) patients failed treatment. Genotypes among these were CRF01_AE (87%), B (11%) and C (2%). TDF-containing regimens had significantly higher failure rates (43/303;14.2%) than AZT-containing regimens (10/209;4.5%) (P < 0.001). Failure rates for NVP-based regimens (13/85;15.3%) vs. EFV-based regimens (40/424; 9.4%) were not significantly different (P = 0.1064). The most durable regimen (with >3 patients) was AZT+3TC+EFV, and the worst regimen was TDF+3TC+NVP (P < 0.001). Failure rates for TDF+3TC+EFV were significantly higher than for AZT+3TC+EFV (P = 0.0029). There was no significant difference in adherence (P = 0.5531). 53% of unsuppressed patients had a TDF-resistance mutation, compared with 8% for AZT (P < 0.001).

Conclusion

TDF-containing regimens were associated with higher treatment failure rates in our CRF01_AE-predominant HIV epidemic. WHO recommendations for treatment may need be revisited for non-B subtypes.

Disclosures

E. M. Salvana, Merck: Scientific Advisor and Speaker’s Bureau, Consulting fee and Speaker honorarium
Impact of Tablet Burden and Antiretroviral Therapy (ART) Choice on Virologic Outcomes in Treatment Naive HIV+ Individuals Attending an Inner City Clinic
Authors: Markowitz Norman , Tidwell Beni , Lamerato Lois , Zelt Susan , D’Amico Ronald , Schulman Kathy
Published: October 2017

Background

The durability and effectiveness of single tablet regimens (STR) in treating ART naïve patients in real world, inner city settings, has not been well established.

Methods

Data was abstracted from administrative/medical records at Henry Ford Health System, serving metropolitan Detroit, for HIV+ patients initiating ART (1/1/2007–9/30/2015), who were enrolled in the Health Alliance Plan (HAP) or had ≥1 clinician contact per year and ≥1 viral load (VL)/CD4 test result ≤90 days prior to ART initiation. Patients were followed from initiation to first of: change in ART, death, HAP disenrollment, study end (03/31/2016), or lost to follow-up. Cox regression estimated impact of tablet burden on ART regimen duration, achievement of viral suppression (VS) and viral failure—(VF) failure to suppress plasma HIV RNA to <50 copies/mL or rebound after VS.

Results

Among 390 eligible patients, 79% were male, 74% African-American. Median (IQR) age was 37 years (27–47), 49% MSM and 22% presented with AIDS. The majority (65%) initiated on an STR; 35% on multiple tablet regimens (MTR). The majority of STR initiators (63%) began with EFV/FTC/TDF; 24% with EVG/c/FTC/TDF; and 8% with DTG/ABC/3TC. The most frequent MTR were DRV+RTV+TDF/FTC (26%) and ATV+RTV+TDF/FTC (20%). Median (IQR) log10 VL at baseline was 4.8 (4.3–5.2) in STR; 4.8 (4.4–5.4) in MTR cohorts. Median CD4 cells/µL (IQR) was 277 (115–407) in STR; 231 (37–371) in MTR. VL suppression occurred in 81% (85% STR, 74% MTR, P < 0.01) of patients and in 91% of INSTI regimens (91% STR, 90% MTR, P = 0.757).VF occurred in 19% (15% STR, 25% MTR, P = 0.015) and in 10% of INSTI regimens (9% STR, 13% MTR,  P = 0.459). Resistance occurred in 15% of VF patients, predominantly with NNRTI mutations. A total of 22% of STR and 60% of MTR initiators experienced a change in their initial ART regimen (P < 0.0001). Cox model results suggest STR initiators were 59% less likely to experience regimen change (P < 0.0001), 46% less likely to experience VF (P < 0.05) and 30% more likely to achieve viral suppression (P < 0.05) compared with MTR initiators.

Conclusion

Inner city, HIV treatment naïve patients, initiating ART with a STR are significantly more likely to achieve viral suppression and less likely to experience a change in ART regimen.

Disclosures

B. Tidwell, ViiV Healthcare: Research Contractor, Research support; L. Lamerato, ViiV Healthcare: Collaborator, Research support; S. Zelt, ViiV Healthcare: Employee and Shareholder, Salary and Stock; R. D’Amico, ViiV Healthcare: Employee and Shareholder, Salary and Stock; K. Schulman, ViiV Healthcare: Research Contractor, Research support
Pharmacokinetics of Cabotegravir in Subjects with Moderate Hepatic Impairment
Authors: Shaik Jafar Sadik , Ford Susan , Lou Yu , Zhang Zhiping , Bakshi Kalpana , Tenorio Allan , Trezza Christine , Spreen William , Patel Parul
Published: October 2017

Background

Cabotegravir (CAB) is an integrase inhibitor in phase 3 clinical trials for the treatment and prevention of HIV. CAB undergoes hepatic metabolism primarily via UGT1A1; thus hepatic impairment has the potential to affect CAB exposure.

Methods

This was a multi-center, single-dose, open-label, parallel group study to evaluate the effect of moderate hepatic impairment on the pharmacokinetics (PK) and safety of CAB. Adults with moderate hepatic impairment as determined by Child-Pugh classification score of 7–9 (n = 8) and matched healthy control subjects (n = 8) were enrolled. Control subjects were matched for gender, age (±10 years), and body mass index (BMI) (±25%). Subjects received oral CAB 30 mg as a single dose in the fasted state followed by serial PK sampling for 168 hours. CAB unbound concentrations at 2 and 24 hours after dosing were determined by equilibrium dialysis. Non-compartmental PK analysis was performed; geometric least squares (GLS) mean ratios (hepatic impaired group/control group) and 90% confidence intervals (CI) were generated.

Results

Sixteen subjects completed study; 12 (75%) male, mean age 59 years (range: 51–67), mean BMI 29 kg/m2 (range: 21–37), and total Child Pugh score in range of 7–9. CAB PK parameters were similar between subjects with moderate hepatic impairment and matched healthy subjects. The GLS mean ratios (90% CI) for AUC(0-∞), Cmax, C24, CL/F, and t1/2 were 0.73 (0.50, 1.06), 0.69 (0.51, 0.93), 0.73 (0.53, 1.02), 1.38 (0.95, 2.01), and 0.82 (0.65, 1.04), respectively. Although highly protein bound, the unbound fraction of CAB was increased in subjects with moderate hepatic impairment relative to healthy subjects with GLS mean ratio (90%CI) of 2.14 (1.57, 2.90) at 2 hours post dose and 1.90 (1.14, 3.18) at 24 hours post dose; this was associated with lower serum albumin concentrations and was not considered clinically significant. All adverse events (AE) were reported as mild (Grade 1) to moderate (Grade 2) in severity and no serious AEs were reported.

Conclusion

Plasma exposures of CAB in subjects with moderate hepatic impairment were similar to those in healthy subjects. No dose adjustment of CAB is required for subjects with mild to moderate hepatic impairment.

Disclosures

J. S. Shaik, GlaxoSmithKline: Employee and Shareholder, Salary; S. Ford, PAREXEL International: Employee, Salary; Y. Lou, PAREXEL International: Employee, Salary; Z. Zhang, PAREXEL International: Employee, Salary; K. Bakshi, GlaxoSmithKline: Employee and Shareholder, Salary; A. Tenorio, ViiV Healthcare: Employee and Shareholder, Salary; C. Trezza, ViiV Healthcare: Employee and Shareholder, Salary; W. Spreen, ViiV Healthcare: Employee and Shareholder, Salary; P. Patel, ViiV Healthcare: Employee and Shareholder, Salary
Pharmacokinetics of Cabotegravir in Subjects with Severe Renal Impairment
Authors: Parasrampuria Ridhi , Ford Susan , Lou Yu , Fu Caifeng , Bakshi Kalpana , Tenorio Allan , Trezza Christine , Spreen William , Patel Parul
Published: October 2017

Background

Cabotegravir (CAB) is an integrase inhibitor in phase 3 clinical trials for the treatment and prevention of HIV. CAB undergoes glucuronidation via UGT1A1 with <1% renal elimination of unchanged CAB. Renal impairment may affect PK of drugs that are primarily metabolized or secreted in bile; thus impact of renal impairment on CAB pharmacokinetics was evaluated.

Methods

This was a multi-center, single-dose study of oral CAB 30mg administered to subjects with severe renal impairment (creatinine clearance [CLcr] <30 mL/minute; not on renal replacement therapy) and to healthy controls (CLcr ≥90 mL/minute) matched for gender, age (±10 years), and body mass index (BMI) (±25%) (8 per group). Serial PK for plasma CAB concentrations were collected through 168 hours post dose and unbound CAB concentrations determined at 2 and 24 hours post dose. Non-compartmental PK analysis was performed; geometric least squares (GLS) mean ratios and 90% confidence intervals (CI) were generated.

Results

Sixteen subjects completed study; 12 (75%) male, mean age 54 years (range:35–69), mean BMI 28 kg/m2 (range: 24–35), and mean CLcr 22 mL/minute (range: 17–29) and 121 mL/minute (range: 95–162) for renal impaired and healthy subjects, respectively. CAB PK parameters were similar between severe renal impairment and healthy subjects. Based on preliminary PK, GLS mean ratios (90% CI) for AUC(0-¥), Cmax, C24, CL/F, and t1/2 were 0.97 (0.835, 1.14), 1.01 (0.865, 1.17), 1.02 (0.868, 1.20), 1.03 (0.881, 1.20) and 0.93 (0.831, 1.04), respectively. Although highly protein bound, the unbound fraction was higher in subjects with severe renal impairment with GLS mean ratio (90%CI) of 1.31 (0.843, 2.03) at 2 hours and 1.51 (1.19, 1.92) at 24 hours post dose. One renal impairment subject developed grade 3 lipase elevation considered drug-related by investigator, otherwise all reported adverse events (AE) were Grade 1 in severity with no serious AEs reported.

Conclusion

Plasma CAB exposures in subjects with severe renal impairment were similar to healthy subjects; therefore, no dose adjustment of CAB is required in renal impairment. Although no data are available, CAB PK is not expected to be affected in subjects undergoing dialysis given CAB’s non-renal clearance and high plasma protein binding (~99%).

Disclosures

R. Parasrampuria, GlaxoSmithKline: Employee and Shareholder, Salary; S. Ford, PAREXEL International: Employee, Salary; Y. Lou, PAREXEL International: Employee, Salary; C. Fu, PAREXEL International: Employee, Salary; K. Bakshi, GlaxoSmithKline: Employee and Shareholder, Salary; A. Tenorio, ViiV Healthcare: Employee and Shareholder, Salary; C. Trezza, ViiV Healthcare: Employee and Shareholder, Salary; W. Spreen, ViiV Healthcare: Employee and Shareholder, Salary; P. Patel, ViiV Healthcare: Employee and Shareholder, Salary
Risk Factors for Pseudomonas aeruginosa in Diabetic Foot Infections
Authors: Farhat Nada , McClung Daniel , Nagel Jerod
Published: October 2017

Background

Infectious Diseases Society of America guidelines for the management of diabetic foot infections (DFIs) suggest 15 different antibiotic treatment options for moderate-to-severe infections. All treatment options provide coverage for Gram-positive cocci, and some provide coverage for Gram-negative pathogens, including Pseudomonas aeruginosa (PSA). However, there is minimal guidance in determining which patients require anti-PSA therapy.

Methods

This single-center retrospective case–control study included patients hospitalized between October 2013 and September 2015. Adult patients admitted with a DFI were identified using a combination of ICD-9 codes for diabetes with complications and cellulitis. The primary outcome was identification of risk factors associated with PSA DFIs. A multivariable model using logistic regression was constructed, and a receiver operator characteristic (ROC) curve was generated to assess the sensitivity and specificity of the model.

Results

262 patients were included and 12 (4.6%) patients had cultures with PSA. Multivariable analysis yielded six risk factors for PSA DFIs (see Table). ROC construction yielded an area under the curve of 0.895.

Conclusion

The incidence of PSA from DFIs is low. A model with excellent performance characteristics demonstrated that risk factors for PSA DFIs include age > 65, BMI ≥ 35, former or current smoker, history of lower extremity bypass procedure, and cardiovascular disease. Future validation of these factors could help stewardship programs reduce unnecessary antibiotic utilization.

Disclosures

All authors: No reported disclosures.
Clinical outcomes associated with once daily ritonavir-boosted darunavir in HIV infected patients harboring single or multi-class resistant virus
Authors: Duggan Joan , Sahloff Eric
Published: October 2017

Background

Limited data exist on the use of a potent boosted protease inhibitor plus <2 active nucleotide reverse transcriptase inhibitors without use of additional classes of ART in treatment experienced patients with background resistance. We evaluated the clinical outcomes in HIV-infected patients harboring single or multi-class resistant virus (NRTI ± PI and/or NNRTI) treated with once daily darunavir/ritonavir (DRV/r) plus tenofovir/emtracitabine (TDF/FTC).

Methods

This was a single-center, retrospective chart review of HIV-1 infected patients harboring single or multi-class resistant virus and receiving an ART regimen of TDF/FTC plus DRV/r administered as a once daily regimen > 24 weeks. The primary outcome was HIV viral load (VL) < 200 copies/mL (cp/mL) at last measurement. Additional endpoints included virologic rebound, re-suppression, and/or failure; VL < 40 cp/mL at last measurement; development of additional mutations. Virologic failure (VF) was defined as failure to achieve a VL < 200 cp/mL or achievement of VL < 200 cp/mL but with rebound to > 200 cp/mL on all successive VLs.

Results

34 of 387 patients meet criteria for inclusion in the study and were receiving DRV 800 mg daily/r 100 mg daily with fixed combination TDF/FTC. All patients had baseline resistance to FTC (M184V/I), 12 (35.3%) had resistance to TDF, and none had high level DRV resistance. 27 (79%) achieved a VL < 200 cp/mL and 25 (74%) had a VL < 200 cp/mL at the last reading. 23 (68%) achieved a VL of < 40 cp/mL. VF occurred in 8/34 patients (24%) with the following baseline parameters: TDF resistance (2/8), low/ intermediate DRV resistance (2/8), and VL > 100,000 cp/mL (3/8). Both patients with baseline DRV resistance and VF demonstrated high level resistance to DRV on repeat genotype testing. Adherence was considered a major contributor to VF.

Conclusion

The use of once daily DRV/r plus TDF/FTC in treatment experienced patients with single/multi-class resistant virus resulted in virologic suppression in over two-thirds of patients. VF was seen in nearly 25% of patients including development of high level DRV resistance. This combination is a potentially viable option in a patient population seeking a once-daily option to improve adherence.

Disclosures

All authors: No reported disclosures.
Application of The Change Point Analysis to The Long-Term Restoration of CD4 Count Among Well-Controlled HIV-1 Infected Patients Who Started Antiretroviral Therapy
Authors: Yoshikazu Mutoh , Nishijima Takeshi , Tanaka Noriko , Inaba Yosuke , Kikuchi Yoshimi , Gatanaga Hiroyuki , Oka Shinichi
Published: October 2017

Background

Although CD4 count is an important marker for prognosis of patients infected with HIV-1, how long and how much CD4 count will increase after initiation of cART are still unknown. Hence, the aim of this study is, using change point analysis, to examine the long-term CD4 count restoration among well-controlled HIV-1 patients.

Methods

In this single-center cohort study at AIDS Clinical Center, Tokyo, we examined HIV-1 infected patients who initiated cART between January 2004 and January 2012 and achieved HIV viral load of <200 copies/mL within first 48 weeks of treatment and maintained viral suppression (VL <200 copies/mL) for at least 4 years. cART was defined as combination regimen which consisted of NNRTI, PI, or INSTI, plus two NRTIs. All patients were followed until censoring (defined by VL >200 copies/mL, discontinuation of cART for >30 days, lost to follow-up for >1 year, initiating chemotherapy for malignancy, or death), or at end of the observation period (September 30, 2015). Change point analysis was performed to determine the time point where the restoration of CD4 count becomes plateau.

Results

Of 752 patients, 708 (94.2%) were male and 89.9% was MSM. The median age was 39.3 years [IQR, 32–45] and the median baseline CD4 count and %CD4 were 172 cells/mm3 [IQR, 61–254], and 13.8% [IQR, 7.7–18.5], respectively. The median follow-up period was 87.0 months [IQR, 65.2–109.2] and 134 were followed over ten years. With change point analysis, both longitudinal increase of CD4 count and %CD4 increased linearly until 78.6 and 62.2 months, respectively. Stratified by baseline CD4 count (<200 cells/mm3, 200–350 cells/mm3, and >350 cells/mm3), CD4 count increased linearly until 76.2, 62.4, and 58.6 months, respectively. Moreover, the percentage of patient who achieved 500 cells/mm3 during study period was 63.5%, 87.2%, and 92.0%, respectively.

Conclusion

With change point analysis, restoration of CD4 count and %CD4 continued increasing linearly until 6.5 and 5 years of cART, respectively. Patients with lower baseline CD4 count showed longer CD4 count recovery than those with higher baseline CD4; however, their CD4 count did not recover as high as those with higher baseline CD4 count.

Disclosures

All authors: No reported disclosures.
Treatment of HIV and Use of HAART in HIV Infected Patients with Acute Septic Shock
Authors: Polk Christopher , Webb Samuel , Rozario Nigel , Moore Charity , Leonard Michael
Published: October 2017

Background

For HIV patients admitted with sepsis, ARVs are often stopped or held due to myriad concerns including drug interactions, acute renal failure, gastrointestinal dysfunction, or inability to administer crushed medications down feeding tubes. We seek to examine prescription patterns of HAART for HIV positive patients admitted for sepsis in our healthcare system and the impact of HAART prescription on patient outcomes.

Methods

We identified HIV positive patients from an institutional database of patients admitted for sepsis within our multi-hospital healthcare system and retrospectively extracted further clinical patient and laboratory information as well as information on HAART prescription by chart review. The impact of HAART prescription and immunologic and virologic parameters of HIV infection on mortality was examined.

Results

Inpatient mortality was 35% in HIV patients admitted for sepsis, compared with 17% for all patients with sepsis in our healthcare system. Opportunistic infections were identified in only 25% of patients while 56% had other infections identified. Only 55% of patients had HAART prescribed while inpatient. CD4 count, virologic suppression, APACHE score, presence of an opportunistic infection, admission to a tertiary care hospital, and inpatient prescription of HAART were all predictors of survival.

Conclusion

Immunologic and virologic status at time of admission predicted survival in HIV patients admitted for sepsis but prescription of HAART to HIV patients admitted for sepsis may increase survival.

Disclosures

C. Polk, Gilead Sciences: Investigator, Research support; Viiv Healthcare: Investigator, Research support
HIV in Ecuador: A Current Perspective of the Epidemics from a Major HIV Care Center.
Authors: Cevallos Leonardo Cano , Cevallos Edison Cano , Vera Andrea Vélez , Suárez Nathalie , Delgado Maryuri , Ollague Xavier Delgado
Published: October 2017

Background

Human Immunodeficiency Virus (HIV) infection is estimated to affect 36.7 million people (persons living with HIV [PLWH]). In Latin America and Caribbean exist around 2 million of PLWH. Ecuador estimates are close to 35.000 PLWH with prevalence of 3 cases per 1000 population, being 31.4% woman. Since the first case of HIV reported in the country in 1983 the efforts have been made to improve prevention and treatment of the disease being epidemiology paramount in planning. Herein we present a current panorama of HIV in Ecuador from a major center serving approximately 2 million people in the coastal zone.

Methods

Patients with diagnosis of HIV/AIDS (ICD-10 B24) from January to December 2015 were included from a database comprising 346.386 visits to outpatient clinics. The variables we consider were demographics, newly vs. previously diagnosed, type of antiretroviral regimen, AIDS-defining conditions, CD4 count and viral load. The statistical analysis was made on Microsoft Excel.

Results

A total of 3776 HIV positive patients were found during the study period. Median age was 37 ± 15, 37 ± 15 for males and 38 ± 15 for females (P > 0.05). Male to female ratio was 4.72:1. More than half patients (2588, 68.5%) were receiving antiretroviral therapy. The most common therapy used was tenofovir + emtricitabine + efavirenz, followed zidovudine + lamivudine + efavirenz for 472 (18.2%). Most patients (91.97%) with HIV infection were not in AIDS stage. Newly diagnosed HIV was seen in 824 patients (21.82%), of which 59 (7%) were on AIDS stage at time of diagnosis. There was only 45 cases in this group (5.46%) with CD4 <200 cells/mm3 possibly suggesting rapid progression or advanced disease.

Conclusion

HIV infection is a public health concern in Ecuador affecting mostly young males. More than half patients are on antiretroviral therapy and most patients are not in AIDS stage. This study comprises a current view of the epidemiological situation of HIV/AIDS in the coast of Ecuador and allows for planning and further research.

Disclosures

All authors: No reported disclosures.
PrEP Uptake and Emergent HIV infections in Southern Arizona: Is There A Disconnect?
Authors: Georgescu Anca , Egurrola Cesar , Schaff Spencer , Fisher Julia , Smith Shannon , Florita Catalin , Guido Alyssa , Klotz Stephen
Published: October 2017

Background

Despite expansion of antiretroviral therapy in recent years and growing evidence for PrEP (pre exposure prophylaxis) efficacy, HIV incidence has continued to rise while PrEP uptake has remained low, particularly in populations at risk. Our goal is to compare these populations and further identify discrepancies in populations at risk in Southern Arizona.

Methods

We retroactively reviewed health records for patients evaluated at Banner University Medical Center Tucson outpatient clinics between January 2014 and September 2016, either with a new HIV diagnosis or prescribed tenofovir/emtricitabine for PrEP.

Results

We identified 147 patients with new HIV diagnoses and 65 patients evaluated for PrEp. 63% of the newly diagnosed HIV were of Hispanic, African American or American Indian descend (46%, 14% and 3% respectively) while the majority of PrEP patients were White (58%) with a statistically significant difference between the groups (P = 0.006). There was no significant difference between the age groups [28 (19%) of the HIV and 13 (20%) of the PrEP were 18–24] or gender (88% of people accessing HIV care were men, vs. 91% men seen for PrEP). Insurance information at the time of presentation was available for 145 HIV and 64 PrEP patients with statistically significant differences between the groups. 31(21%) newly diagnosed HIV had no insurance and 71 (49%) had a Medicaid plan while 45 (70%) of PrEP patients has a private insurance plan (P < 0.001). None of the people accessing PrEP reported iv drug use as a risk factor compared with 16 (11%) of the newly diagnosed (P = 0.003). Retention in care at 3 months was similar (76% of HIV and 75% of PrEP). The predominant risk categories were MSM with multiple partners and/or condomless anal sex for both groups.

Conclusion

To our knowledge this is the first study evaluating HIV and PrEP health care disparities in a border region of the Southwestern US, which is home to a large Hispanic minority population. Our findings suggest that low income minority populations, such as Hispanic, African American and American Indian in this region continue to have a higher risk for HIV acquisition and highlights the ongoing need to expand research on how these populations perceive their risk for HIV and navigate complex systems, such as health insurance, when seeking clinical services for PreP.

Disclosures

All authors: No reported disclosures.
A Novel Vancomycin Standardized Calculations Method Achieved Therapeutic Trough Goals in Obese and Non-obese Patients in a Veterans Affairs Health Care System
Authors: Foral Pamela , Dalke Brian , Brondum Ashley , Hrdy Michaela , Horne John , Destache Christopher
Published: October 2017

Background

Pharmacokinetic dosing of vancomycin in obese patients has not been standardized. Limited literature is available on appropriate dosing of vancomycin in this increasing population. We evaluated the utilization and impact of a standardized calculation method (SCM) in obtaining therapeutic vancomycin levels.

Methods

A SCM, including the use of an adjusted body weight for dosing and volume of distribution in obese patients, was implemented at our institution April 2014. Retrospective medical records review of hospitalized patients with a vancomycin steady-state trough level pre- (February 2013 to March 2014) and post-implementation (June 2014 to July 2015) of the SCM. Patients with dialysis, paraplegia/quadriplegia, vancomycin level drawn < 48 hours of admit, trough level drawn > 2 hours prior to next dose, during or after vancomycin infusion were excluded. Appropriateness of vancomycin levels were evaluated between the pre- (PreG) and post-groups (PostG), as well as BMI classification. Nephrotoxicity was defined as a rise in serum creatinine > 0.5 mg/dl or > 50% from baseline during or up to 72 hours after stopping vancomycin therapy. Appropriate statistical tests were analyzed using SPSS-PC (ver. 24, Chicago, IL).

Results

There were no significant differences in the PreG (n = 97) and PostG (n = 97) for age, gender, length of vancomycin therapy, and non-obese and obese patients. In the PostG, significant improvement in the overall use of the SCM (P < 0.001) was determined. Other significant (P < 0.001) factors associated with vancomycin patient management in the PostG were found. There was an overall significant improvement in achieving a therapeutic trough goal of 10–20 (±1 mcg/ml) in BMI classes, predominantly in BMI Class 4 PreG 26% and PostG 74%, P < 0.05. More patients in the PreG (11) had the first trough >21 mcg/ml than the PostG, (4), P = 0.104. Patients who developed nephrotoxicity included PreG 15% and 0% PostG, P = 0.115.

Conclusion

SCM of vancomycin regimens resulted in a significant improvement in obtaining therapeutic trough levels overall, including the obese BMI class 4. Defined nephrotoxicity was absent in the PostG group.

Disclosures

All authors: No reported disclosures.
Spatio-temporal Activity of Human-Simulated Exposures of Meropenem (MEM) and Ceftolozane (TOL) on Pseudomonas aeruginosa Biofilms
Authors: Rajan Srijay , Verotta Davide , Sutherland Christina , Nicolau David P , Spormann Alfred , Yang Katherine
Published: October 2017

Background

TOL and MEM possess in vitro activity against P. Aeruginosa grown in planktonic culture. Less is known about the activity of TOL and MEM on antibiotic-tolerant biofilms, such as those residing in the lungs of cystic fibrosis (CF) patients. The objective of this study is to compare the spatial and temporal activity of TOL and MEM on early and mature P. Aeruginosa biofilms grown in flow-chambers.

Methods

PAO1 and a clinical strain (strA) isolated from a child with CF were used. Isolates were cultivated in flow-chambers for 24 or 72 hours. Early (24-hours) biofilms were treated with the simulated human concentrations of 1 dose of either 2 g of TOL or MEM. Peak concentrations were 150 mg/L and 107.53 mg/L for TOL and MEM. Mature (72-hours) biofilms were treated with 3 doses of MEM or TOL administered every 8 hours. Images were acquired during antibiotic treatment using confocal laser scanning microscopy. Images were processed with Imaris and analyzed using COMSTAT 2.0. Pharmacodynamic modeling was performed with NONMEM.

Results

PAO1 and strA were susceptible to TOL and MEM per CLSI guidelines. Kill rates for TOL and MEM are shown below. TOL displayed smaller killing rates compared with MEM for early biofilms; TOL and MEM showed similar activity against the mature clinical strain (strA). MEM and TOL were less effective against strA compared with PAO1.

Conclusion

TOL and MEM displayed similar spatial activity against P. Aeruginosa biofilms grown in flow-chambers. Temporal differences in kill rates and bacterial recovery between TOL and MEM may inform future dosing strategies for biofilm-associated infections such as CF.

Disclosures

D. Verotta, Merck: Grant Investigator, Grant recipient. D. P. Nicolau, Merck: Investigator and Speaker’s Bureau, Research support. K. Yang, Merck: Grant Investigator, Grant recipient.
Incidence of Nephrotoxicity Among Patients Initiated on Vancomycin and Β-lactam Combination Therapies
Authors: Shah Megha , Rajasimhan Suraj , Bias Tiffany
Published: October 2017

Background

Vancomycin and β-lactam combinations are used to provide empiric coverage in hospitalized patients. Recent literature has illustrated an increased incidence of nephrotoxicity with such combinations, predominantly with piperacillin-tazobactam and vancomycin. The objective of this study is to evaluate the incidence of nephrotoxicity among patients receiving vancomycin and piperacillin-tazobactam vs., cefepime, or aztreonam.

Methods

A retrospective, observational, cohort study was conducted at Hahnemann University Hospital in adult patients who received vancomycin plus piperacillin-tazobactam, cefepime, or aztreonam for at least 48 hours between June 2013 and August 2016. Patients were excluded if they had chronic kidney disease Stage III or higher or on continuous renal replacement therapy. The following data were collected: demographics, renal function, number of concomitant nephrotoxic agents, total duration of combination therapy, and vancomycin levels. The primary outcome was the incidence of nephrotoxicity according to the Risk Injury Failure End Stage Renal Disease (RIFLE) criteria. Secondary outcomes were the total length of hospital (LOS) and intensive care unit (ICU) LOS. Statistical analyses were conducted using the Analysis of Variance and the Chi-square test.

Results

A total of 757 charts were reviewed of which 203 were included in the analysis; 69 in the piperacillin-tazobactam arm, 74 in the cefepime arm, and 60 in the aztreonam arm. The incidence of nephrotoxicity as assessed by the RIFLE criteria was higher in the piperacillin-tazobactam arm (41%) compared with cefepime (15%) and aztreonam arms (17%); P = 0.052. Majority of patients with nephrotoxicity experienced injury according to the RIFLE criteria. No differences were found in the total LOS, ICU LOS, or duration of nephrotoxicity. Patients who experienced nephrotoxicity in the piperacillin-tazobactam arm occurred earlier upon antibiotic initiation at 48 hours compared with the other arms extending past 72 hours; P = 0.004.

Conclusion

There was a trend towards more patients experiencing nephrotoxicity in the piperacillin-tazobactam arm compared with the other groups. Clinicians should remain vigilant when utilizing combination therapy.

Disclosures

T. Bias, Merck: Grant Investigator, Research grant. The Medicines Company: Speaker’s Bureau, Speaker honorarium.
Creation and Validation of a Pediatric Vancomycin Nomogram for a Goal Trough of 10–15 mg/L at a Quaternary Care Children’s Hospital
Authors: Lee Philip , Frye Jessica , Chen Xing , Chang Susanna , Singh Birender , Soma Vijaya
Published: October 2017

Background

Recent data suggest a serum vancomycin (vanc) trough (VT) of 11mg/L correlates with an AUC/MIC24 > 400 which has shown to be the optimal concentration to eradicate MRSA infection and improve mortality. There are currently limited published recommendations on how to achieve such a VT in children. This study validates a vancomycin nomogram used to achieve a VT of 10–15 mg/L in pediatric inpatients (pts) at a quaternary care children’s hospital.

Methods

This is an 18 month (mo) prospective analysis beginning in September 2015. Included pts were ≥2 mo of age and had ≥2 consecutive VT. Pts receiving renal replacement therapy or those with a serum creatinine (Scr) of ≥0.5 mg/dL from a prior admission or within 48 hours of vanc initiation were excluded. The starting dose (SD) of vanc was determined by age and creatinine clearance (CrCl) (Tables 1 and 2). CrCl was measured by Bedside Schwartz equation for patients ≤18 years old (yo) and Cockcroft-Gault equation for patients >18 yo. The maximum CrCl was set to 120 ml/minute. Patients who were on vanc and experienced a Scr increase of ≥0.5 mg/dL were considered to have acute kidney injury (AKI). The study had a 6 mo evaluation period which led to a revised version (RVN) on March 2016. The primary endpoint (PE) was achievement of 10–15 mg/L by the Second VT for patients with the First trough outside of this range, using our RVN (Table 3).

Results

Overall, a total of 276 patients received vanc, 17 and 29 patients were dosed according to the initial and RVN, respectively. For young children (Table 1), the SD for patients with a CrCL ≥90 ml/minute was therapeutic, sub-, and supra-therapeutic in 43.75%, 47.5% and 8.75%, respectively. For older children (Table 2), the SD for patients with a CrCl ≥100 ml/minute was therapeutic, sub-, and supra-therapeutic in 41.1%, 35.7% and 23.2%, respectively. The initial VN was successful 12/17 (70.6%) in achieving the PE. Success in achieving the PE after the RVN was 26/29 (89.7%). In the RVN group, the most common initial troughs were 5–7 mg/L (33.3%), followed by >18 mg/L (27.6%). The mean VT using the RVN was 13.7 mg/L. The overall AKI incidence throughout the study was 3.2% (9/276) and 0% using the RVN.

Conclusion

Our RVN led to a Second VT within a target range of 10–15 mg/L for 89.7% of patients, allowing for more accurate and safer use of vancomycin in our institution.

Disclosures

All authors: No reported disclosures.
Viral Infections of the Central Nervous System in Qatar: Epidemiology, Pathogenesis and Clinical Outcomes
Authors: Abid Fatma Ben , Abukhattab Mohammed , Salameh Obada , Gohar Ahmed , Al Masalmani Muna , Al-Khal Abdullatif , Butt Adeel
Published: October 2017

Background

Viral central nervous system (CNS) infections are common causes of morbidity and mortality globally. There are no existing data about viral CNS infections in Gulf Cooperation Council countries. We conducted this study to determine the etiology, clinical and epidimiological characteristics, and outcomes of viral central nerveous system infection in patients in Qatar.

Methods

We retrospectively evaluated all cerebrospinal fluid findings from January 2011–March 2015 at any of the 7 hospitals in the Hamad Medical Corporation. We included those with an abnormal CSF findings and excluded those with missing medical records, no clinical evidence of CNS infection and those with proven bacterial infection. Based on pre-defined clinical and CSF (lab, culture, PCR) criteria, patients were classified as having meningitis, meningoencephalitis, encephalitis or myelitis. We reviewed the laboratory results to determine the proportion of persons with confirmed viral etiology.

Results

Among 7690 patients with available CSF results, 550 cases met the case definition criteria for viral CNS infection (meningitis 75%; meningoencephalitis 16%; encephalitis 9%; myelitis 0.4%). Two-thirds (65%) were male and 50% were between 16-60 years old. The most common presenting signs and symptoms are listed in the table. Persons of Southeast Asian origin accounted for 39.6% of all infections. A definitive virologic etiologic agent was found in 38%, with enterovirus being the most common (44.3%) followed by Epstein–Barr virus (31%) and varicella-zoster virus (12.4%). The clinical outcome was overall good, only 2 cases died and the rest were discharged to home. Among those with confirmed viral etiology, 83.8% received ceftriaxone (mean duration 7.3 ± 5.2 days), 38% received vancomycin (mean duration 2.7 ± 5.4 days) and 38% received at least one other antibiotic.

Conclusion

Viral etiology is common among those evaluated for CNS infection in Qatar, and is most commonly seen in Southeast Asian immigrants. Clinical outcomes are generally excellent in this group of patients. Antibiotics are overly used even when a viral etiology is confirmed. There is a need for clinician education regarding etiology and treatment of CNS infections.

Disclosures

A. Butt, Merck: Investigator, Grant recipient
Implementation of In-house PCR Testing for Herpes Simplex Virus Encephalitis: Impact on Patient Acyclovir Exposure
Authors: Beaulieu Ronald , Veron Katie , Hamer Diana , O’Neal Catherine , O’neal Hollis
Published: October 2017

Background

HSV encephalitis is a life-threatening disease process that requires prompt treatment. Diagnosis is often dependent upon nucleic acid studies of CNS samples. We introduced the Film Array Meningitis/Encephalitis (ME) Panel, a qualitative multiplexed nucleic acid-based diagnostic test for a variety of CNS pathogens, including HSV, in June 2016. It replaced an equivalent reference laboratory nucleic acid amplification test. The intent was to provide a more timely result and decrease unnecessary drug exposure to the patient.

Methods

We conducted a retrospective chart review of adult patients (>18 yo) admitted between June-September 2015 and June-September 2016 who underwent CSF testing for HSV and received empiric acyclovir. The aim was to determine whether the newly available test resulted in fewer doses of acyclovir in those who tested negative for a herpes virus as compared with those tested with the previously available assay. We excluded those found to be positive for HSV-1, HSV-2, or VZV in the CSF. We defined a dose as any administration of acyclovir or valacyclovir to the patient.

Results

Results of the diagnostic assay returned significantly faster after institution of the ME panel (4.9 days (118 hours) vs .09 days (2.25 hours)). Due to the non-normal distribution of acyclovir dosing, comparisons were made with the Wilcoxson Rank-sum. The institution of the ME panel for all CSF studies significantly impacted our use of acyclovir, as patients with negative tests for HSV PCR in the CSF received fewer doses of acyclovir after implementation of the ME panel (median (25th–75th percentiles) 6 (2–13.5) vs 3 (1–6), P = .018).

Conclusion

Implementation of a rapid diagnostic PCR based test for HSV 1 and HSV 2 in 2016 significantly reduced the number of empiric acyclovir doses administered during the summer of 2016 compared with the summer of 2015 in patients testing negative for the condition.

Disclosures

All authors: No reported disclosures.
Phase 1 Clinical Trial of a Replication-Defective Human Cytomegalovirus (CMV) Vaccine
Authors: Adler Stuart , Lewis Nicole , Conlon Anthony , Christiansen Mark , Al-Ibrahim Mohamed S , Rupp Richard , Fu Tong Ming , Bautista Oliver , Tang Huaping , Culp Timothy , Das Rituparna , Beck Karen , Tamms Gretchen , Musey Luwy
Published: October 2017

Background

Congenital CMV remains an unmet medical need worldwide. Naturally acquired CMV immunity in women prior to pregnancy has been shown effective in reducing maternal-fetal transmission. V160 is engineered as a replication-defective CMV, and its replication in culture is controlled by a synthetic chemical. V160 can’t replicate in humans but it maintains all virological properties for presentation of viral antigens, including gH/gL/pUL128-131 pentameric complex, important for potent neutralizing antibodies (NABs).

Methods

Approximately 190 CMV seronegative and seropositive adults at study entry received 3 doses of V160 or placebo administered via intramuscular (IM) or intradermal (ID) route on Day 1, Month 1, and Month 6. Four antigen levels (10, 30, 100, and 250 units per dose) formulated with or without aluminum phosphate adjuvant were evaluated. In each vaccination group, approximately 10 and 4 subjects received study vaccine and placebo, respectively. Injection site and systemic adverse events (AEs) were collected for 14 days after each vaccination. Serious AEs (SAEs) were assessed up to Month 18. Viral shedding (urine and saliva) were monitored up to Month 12. CMV-specific NABs and cell-mediated immune responses (CMI) were measured prior and 1 month after each vaccination, and at Months 12 and 18.

Results

During the study, no serious AEs were reported and only one CMV seropositive subject had non-vaccine type viral shedding. In both seronegative and seropositive cohorts, proportion of subjects who reported injection site AEs was higher in V160 recipients than placebo controls. Proportion of subjects who reported systemic AEs was comparable across V160 doses/formulations and placebo. In the CMV seronegative cohort, immune responses increased with incremental dosing. More importantly, recipients of V160 from several dose levels mounted NAB and CMI responses at 1 month post dose 3 (PD3) that were comparable to baseline levels measured in seropositive subjects.

Conclusion

V160 had acceptable safety profile across all dose levels and formulations studied; Vaccine was immunogenic and elicited NAB and CMI responses at 1 month PD3 that were comparable to natural CMV infection.

Disclosures

S. Adler, Merck: Investigator, Research grant. N. Lewis, Merck: Employee, Salary. A. Conlon, Merck: Employee, Salary. M. Christiansen, Merck: Investigator, Research grant. M. S. Al-Ibrahim, Merck: Investigator, Research grant R. Rupp, Merck: Investigator, Research grant. T. M. Fu, Merck: Employee, Salary. O. Bautista, Merck: Employee, Salary. H. Tang, Merck: Employee, Salary.T. Culp, Merck: Employee, Salary. R. Das, Merck: Employee, Salary. K. Beck, Merck: Employee, Salary. G. Tamms, Merck: Employee, Salary. L. Musey, Meck: Employee, Salary.
Estimating the Health and Economic Impact of Universal Varicella Vaccination in Jordan
Authors: Hayajneh Wail , Al Abdullat Mohammad , Al Shurman Abdalla , Maalouf Jihane , Kuter Barbara , Weiss Tracey , Daniels Vince , Wolfson Lara
Published: October 2017

Background

To evaluate the impact of adding universal varicella vaccination (UVV) to the existing childhood vaccination programme in Jordan, and identify the most cost-effective strategy.

Methods

A dynamic transmission model of varicella infection was calibrated to available varicella seroprevalence data within the region and validated against local epidemiological data. Local direct and indirect costs and healthcare utilization data were used. We considered the health and economic impact of one dose UVV administered concurrently with MMR at 12 months of age with 95% coverage, and two dose strategies with short (6 month) and long (4 year) intervals between First and Second dose. We took the societal perspective (direct and indirect costs) and discounted costs and QALYs by 3%/year to assess cost-effectiveness.

Results

The model estimated the current burden of varicella at 172,000 cases/year, an incidence rate of 2,200/100,000 persons. In the 5th/25th year after vaccination, all strategies substantially reduced total varicella incidence by 89.5%/96.6% (1 dose), 92.3%/98.0% (2 dose short), and 90.5%/98.3% (2 dose long), compared with no vaccine (Figure 1). In the absence of vaccination, an estimated $47.89 M ($28.81 M direct, $19.08 indirect) was spent annually on varicella treatment. The average annual total treatment costs over 25 years from the societal perspective were $4.01M (1 dose), $3.34M (2 dose short), and $3.43M (2 dose long). Considering a willingness to pay (WTP) threshold of $3,600 USD / QALY and the societal perspective, the 1 dose program was the most cost-effective with cost savings of $83.40 USD and health gain of 4.127 × 10−5 QALYs per person. 2 dose programs are similarly cost-saving and highly effective, compared with a scenario of no vaccination; however, moving incrementally from a 1 dose strategy, incremental cost-effectiveness ratios (ICERS) were $6.9M/QALY (short vs. 1 dose) and $13.5M/QALY (long vs. short), both well as above the WTP threshold. All strategies reached.

Conclusion

One or two dose UVV in Jordan will significantly reduce varicella disease burden and is cost saving relative to no vaccine over 25 years.

Disclosures

W. Hayajneh, Merck & Co., Inc.: Consultant, Consulting fee. J. Maalouf, Merck & Co., Inc.: Employee, Salary. B. Kuter, Merck & Co., Inc.: Employee, Salary.T. Weiss, Merck & Co., Inc.: Employee, Salary. V. Daniels, Merck & Co., Inc.: Employee, Salary. L. Wolfson, Merck & Co., Inc.: Employee, Salary.
Etiologic Involvement of Enterovirus and Human Bocavirus in Acute Flaccid Paralysis Cases in India
Authors: Baluni Manjari , Singh Dharamveer , Ghildiyal Sneha , Fatima Tanzeem , Zia Amreen , Dhole Tapan
Published: October 2017

Background

Acute flaccid paralysis (AFP), characterized by the rapid onset of asymmetric paralysis, can be caused by a variety of viral infections or coinfections. Besides wild-type and revertant vaccine strains of polioviruses, several nonpolio enteroviruses, have also been associated with AFP. Enteroviruses (EVs) are RNA viruses in the family Picornaviridae comprising more than 100 serotypes that are divided into four species, human enteroviruses A to D. The clinical manifestations of EVs range from conjunctivitis, respiratory tract infection, myocarditis, meningitis, encephalitis, and neonatal sepsis, like illness. Human Bocavirus (HBoV), a newly classified member of the Parvoviridae family, has been detected frequently in feces of diarrhoeic children suggesting its possible etiological involvement in the disease.

Methods

Total 586 stool specimens were collected in 2016 from children suspected for AFP. Molecular method for targeting 5’ untranslated region (UTR) and VP1 capsid region was used for detection of human enteroviruses (HEV), human boca viruses (HBoV) and saffold viruses in direct clinical specimen.

Results

EV RNA was detected in 103 (17.6%) of 586 stool specimens by real-time RT-PCR targeting the highly conserved 5’ UTR region. Out of them, 71 (12.11%) were NPEV, partially sequenced by VP1 which revealed the prevalence of echovirus (ECV) 19 (n = 6), ECV 11 (n = 7), ECV 18 (n = 4), ECV 33 (n = 5), ECV 29 (n = 1), ECV 25 (n = 2), ECV 24 (n = 3), ECV 3 (n = 3), ECV 14 (n = 2), ECV 13 (n = 1), ECV 2 (n = 1), ECV 20 (n = 2), ECV 27 (n = 4), ECV 6 (n = 2), CV A10 (n = 2), CV A9 (n = 1), CV A6 (n = 2), CV B4 (n = 1), CV B5 (n = 3), CV B6 (n = 3), EV 80 (n = 1), EV 83 (n = 1), EV 97 (n = 2).

Total 63 (10.75%) HBoVs were detected by real-time PCR which were further sequenced by VP1, consists of HBoV-1 (n = 8), HBoV-2 (n = 15), HBoV-3 (n = 9) and HBoV-4 (n = 5). Out of them 9 (1.5%) were detected as co infection with NPEVs. Phylogenetic analysis showed 0.9 - 5.6% divergence at nucleotide level among HBoVs.

Total 9 (1.5%) saffold viruses was detected and characterized by VP1 sequencing.

Conclusion

ECV and HBoV were found the main etiologic agent in children suspected with AFP. Molecular typing of these viruses is useful for characterizing emerging serotypes and their epidemiological investigation.

Disclosures

All authors: No reported disclosures.