Archive for January 30, 2016

Zika Virus Spreads to New Areas — Region of the Americas, May 2015–January 2016

MMWR Morb Mortal Wkly Rep 2016;65:56–9

Morgan Hennessey, DVM; Marc Fischer, MD; J. Erin Staples, MD, PhD.





January 30, 2016 at 10:44 am

Toxicity of Amphotericin B Deoxycholate-Based Induction Therapy in Patients with HIV-Associated Cryptococcal Meningitis

Antimicrobial Agents and Chemotherapy December 2015 V.59 N.12 P.7224-7231

Tihana Bicanic, Christian Bottomley, Angela Loyse, Annemarie E. Brouwer, Conrad Muzoora, Kabanda Taseera, Arthur Jackson, Jacob Phulusa, Mina C. Hosseinipour, Charles van der Horst, Direk Limmathurotsakul, Nicholas J. White, Douglas Wilson, Robin Wood, Graeme Meintjes, Thomas S. Harrison, and Joseph N. Jarvis

aInstitute of Infection and Immunity, St. George’s University of London, London, United Kingdom

bFaculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, United Kingdom

cElisabeth Hospital, Tilburg, the Netherlands

dMbarara University of Science and Technology, Mbarara, Uganda

eUniversity of North Carolina Project, Lilongwe, Malawi

fMahidol-Oxford Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand

gCentre for Tropical Medicine and Global Health, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom

hEdendale Hospital, Pietermaritzburg, South Africa

iDesmond Tutu HIV Centre, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa

jDivision of Infectious Diseases and HIV Medicine, Department of Medicine, University of Cape Town, Cape Town, South Africa

kInstitute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa

lDepartment of Clinical Research, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom

mBotswana-UPenn Partnership, Gaborone, Botswana

nDivision of Infectious Diseases, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA

Amphotericin B deoxycholate (AmBd) is the recommended induction treatment for HIV-associated cryptococcal meningitis (CM). Its use is hampered by toxicities that include electrolyte abnormalities, nephrotoxicity, and anemia.

Protocols to minimize toxicity are applied inconsistently. In a clinical trial cohort of AmBd-based CM induction treatment, a standardized protocol of preemptive hydration and electrolyte supplementation was applied.

Changes in blood counts, electrolyte levels, and creatinine levels over 14 days were analyzed in relation to the AmBd dose, treatment duration (short course of 5 to 7 days or standard course of 14 days), addition of flucytosine (5FC), and outcome.

In the 368 patients studied, the hemoglobin levels dropped by a mean of 1.5 g/dl (95% confidence interval [CI], 1.0 to 1.9 g/dl) following 7 days of AmBd and by a mean of 2.3 g/dl (95% CI, 1.1 to 3.6 g/dl) after 14 days.

Serum creatinine levels increased by 37 μmol/liter (95% CI, 30 to 45 μmol/liter) by day 7 and by 49 μmol/liter (95% CI, 35 to 64μmol/liter) by day 14 of AmBd treatment. Overall, 33% of patients developed grade III/IV anemia, 5.6% developed grade III hypokalemia, 9.5% had creatinine levels that exceeded 220 μmol, and 6% discontinued AmBd prematurely.

The addition of 5FC was associated with a slight increase in anemia but not neutropenia. Laboratory abnormalities stabilized or reversed during the second week in patients on short-course induction. Grade III/IV anemia (adjusted odds ratio [aOR], 2.2; 95% CI, 1.1 to 4.3; P = 0.028) and nephrotoxicity (aOR, 4.5; 95% CI, 1.8 to 11; P = 0.001) were risk factors for 10-week mortality.

In summary, routine intravenous saline hydration and preemptive electrolyte replacement during AmBd-based induction regimens for HIV-associated CM minimized the incidence of hypokalemia and nephrotoxicity. Anemia remained a concerning adverse effect.

The addition of flucytosine was not associated with increased neutropenia. Shorter AmBd courses were less toxic, with rapid reversibility.



January 30, 2016 at 8:48 am

Tedizolid Population Pharmacokinetics, Exposure Response, and Target Attainment

Antimicrobial Agents and Chemotherapy November 2014 V.58 N.11 P.6462-6470

Flanagan, J. Passarell, Q. Lu, J. Fiedler-Kelly, E. Ludwig, and P. Prokocimer

aCubist, San Diego, California, USA

bCognigen Corporation, Buffalo, New York, USA

Tedizolid phosphate is a novel antibacterial prodrug that is rapidly and extensively converted to its active moiety, tedizolid. We developed a population pharmacokinetics (PK) model for tedizolid using pooled data from seven densely and sparsely sampled clinical trials evaluating oral and intravenous tedizolid.

Model-derived exposure estimates were evaluated for relationships to select efficacy and safety outcomes. A two-compartment model with sigmoidal absorption, absolute bioavailability, and linear elimination described the PK data well.

Variability was small (clearance, 31% coefficient of variation; volume, 13.4% coefficient of variation), and absolute bioavailability was high (86%). No clinically significant covariate effects on tedizolid PK were found.

Based on phase 3 data evaluating 200-mg once-daily tedizolid for acute bacterial skin and skin structure infections (ABSSSI), no relationships were seen between various efficacy outcomes and estimated tedizolid exposure; the estimated exposure range (free-drug area under the concentration-time curve over 24 h at steady state [AUCss(0–24)], 7 to 50 μg · h/ml) in these patients was modest.

Safety data modeling, using once-daily doses of up to 400 mg, showed a small increase in the probability of an adverse event with increasing model-estimated tedizolid exposure; no such relationship was observed when specifically evaluating the 200-mg dose.

There were no trends in neutrophil or platelet counts with increasing tedizolid exposure.

Target attainment simulations for 200-mg tedizolid indicated a 98.31% probability of attaining the target measure (AUC for the free, unbound fraction of a drug [fAUC]/MIC = 3) against a Staphylococcus aureus strain for which the MIC was ≤0.5 μg/ml.

These findings support 200-mg tedizolid once daily as the optimum dose for treatment of ABSSSI.



January 30, 2016 at 8:46 am

Pharmacokinetics of Tedizolid in Subjects with Renal or Hepatic Impairment

Antimicrobial Agents and Chemotherapy November 2015 V.58 N.11 P.6471-6476

Flanagan, S. L. Minassian, D. Morris, R. Ponnuraj, T. C. Marbury, H. W. Alcorn, E. Fang, and P. Prokocimer

aCubist, San Diego, California, USA

bMinassian Biostatistics, Inc., San Diego, California, USA

cCovance, Madison, Wisconsin, USA

dOrlando Clinical Research Center, Orlando, Florida, USA

eDaVita Clinical Research, Minneapolis, Minnesota, USA

Two open-label, single-dose, parallel-group studies were conducted to characterize the pharmacokinetics of the novel antibacterial tedizolid and the safety of tedizolid phosphate, its prodrug, in renally or hepatically impaired subjects.

Tedizolid pharmacokinetics in subjects with severe renal impairment without dialysis support was compared with that of matched control subjects with normal renal function.

Effects of hemodialysis on tedizolid pharmacokinetics were determined in a separate cohort of subjects undergoing long-term hemodialysis.

Effects of hepatic impairment on tedizolid pharmacokinetics were determined in subjects with moderate or severe hepatic impairment and compared with those of matched control subjects with normal hepatic function.

Each participant received a single oral (hepatic impairment) or intravenous (renal impairment) dose of tedizolid phosphate at 200 mg; hemodialysis subjects received two doses (separated by 7 days), before and after dialysis, in a crossover fashion.

The pharmacokinetics of tedizolid was similar in subjects with severe renal impairment and controls (∼8% lower area under the concentration-time curve [AUC], with a nearly identical peak concentration) and in subjects undergoing hemodialysis before and after tedizolid phosphate administration (∼9% lower AUC, with a 15% higher peak concentration); <10% of the dose was removed during 4 h of hemodialysis.

Tedizolid pharmacokinetics was only minimally altered in subjects with moderate or severe hepatic impairment; the AUC was increased approximately 22% and 34%, respectively, compared with that of subjects in the control group.

Tedizolid phosphate was generally well tolerated in all participants. These results suggest that tedizolid phosphate dose adjustments are not necessary in patients with any degree of renal or hepatic impairment.

(This study has been registered at under registration numbers NCT01452828 [renal study] and NCT01431833 [hepatic study].)


January 30, 2016 at 8:43 am

Telavancin for Hospital-Acquired Pneumonia: Clinical Response and 28-Day Survival

Antimicrobial Agents and Chemotherapy April 2014 V.59 N.4 P.2030-2037

Ralph Corey, Marin H. Kollef, Andrew F. Shorr, Ethan Rubinstein, Martin E. Stryjewski, Alan Hopkins, and Steven L. Barriere

aDepartment of Medicine, Duke Clinical Research Institute, Durham, North Carolina, USA

bPulmonary and Critical Care Division, Washington University School of Medicine, St. Louis, Missouri, USA

cPulmonary and Critical Care Medicine, Washington Hospital Center, Washington, DC, USA

dUniversity of Manitoba, Winnipeg, Manitoba, Canada

eDepartment of Medicine, Section of Infectious Diseases, Centro de Educación Médica e Investigaciones Clínicas Norberto Quirno, Buenos Aires, Argentina

fTheravance, Inc., South San Francisco, California, USA

U.S. Food and Drug Administration draft guidance for future antibiotic clinical trials of bacterial nosocomial pneumonia recommends the use of diagnostic criteria according to American Thoracic Society/Infectious Diseases Society of America (ATS/IDSA) guidelines and the use of a primary endpoint of 28-day all-cause mortality.

The effect of applying these guidelines on outcomes of phase III nosocomial pneumonia studies of telavancin was evaluated in a post hoc analysis. ATS/IDSA criteria were applied in a blind fashion to the original all-treated (AT) group. Clinical cure rates at final follow-up were determined in the refined AT and clinically evaluable (CE) groups (ATS/IDSA-AT and ATS/IDSA-CE, respectively).

The exploratory endpoint of 28-day survival was evaluated for the ATS/IDSA-AT group. Noninferiority of telavancin versus vancomycin was demonstrated, with similar cure rates in the ATS/IDSA-AT (59% versus 59%) and ATS/IDSA-CE (83% versus 80%) groups.

Cure rates favored telavancin in ATS/IDSA-CE patients where Staphylococcus aureus was the sole pathogen (86% versus 75%). Overall, 28-day survival rates were similar in the telavancin (76%) and vancomycin (77%) groups but lower in telavancin-treated patients with preexisting moderate-to-severe renal impairment (creatinine clearance [CLCR] of <50 ml/min).

Telavancin should be administered to patients with moderate-to-severe renal impairment only if treatment benefit outweighs the risk or if no suitable alternatives are available.


January 30, 2016 at 8:40 am


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