New drugs and medical issues 2014 {2}

NEW DRUGS
AND MEDICAL ISSUES
2014
SAMIR EL ANSARY

Zerbaxa (ceftolozane and tazobactam)
Injection
Company: Cubist Pharmaceuticals, Inc.
Date of Approval: December 19, 2014
Treatment for: Intraabdominal Infection, Urinary
Tract Infection
Zerbaxa (ceftolozane and tazobactam) is a
cephalosporin and beta-lactamase inhibitor
combination for the treatment of complicated intra-
abdominal infections (cIAI) and complicated urinary
tract infections (cUTI).

Rapivab (peramivir) Injection
Company: BioCryst Pharmaceuticals, Inc.
Treatment for: Influenza
Rapivab (peramivir) is an influenza virus
neuraminidase inhibitor indicated for the
treatment of acute uncomplicated influenza in
adults.
FDA Approves Rapivab (peramivir) to Treat Influenza Infection - December 22, 2014

Saxenda (liraglutide) Injection
Company: Novo Nordisk Inc.
Treatment for: Obesity
Saxenda (liraglutide) is a once-daily glucagon-
like peptide-1 (GLP-1) analogue for the
treatment of obesity.
FDA Approves Saxenda (liraglutide [rDNA origin] injection) for
Obesity - December 23, 2014

Namzaric (donepezil and memantine)
Company: Actavis plc and Adamas Pharmaceuticals Inc.
Treatment for: Alzheimer's Disease
Namzaric (memantine hydrochloride extended-release
and donepezil hydrochloride) is an NMDA receptor
antagonist and acetylcholinesterase inhibitor fixed-dose
combination for the treatment of moderate to severe
Alzheimer’s disease.

Viekira Pak
(ombitasvir/paritaprevir/ritonavir with
dasabuvir) Tablets
Company: AbbVie Inc.
Treatment for: Chronic Hepatitis C
Viekira Pak (ombitasvir/paritaprevir/ritonavir with
dasabuvir) is an NS5A inhibitor, NS3/4A protease
inhibitor and CYP3A inhibitor combination co-packaged
with a non-nucleoside NS5B palm polymerase inhibitor
for the treatment of patients with genotype 1 chronic
hepatitis C virus (HCV) infection.

(tobramycin) Inhalation
Solution
Company: PulmoFlow, Inc.
Treatment for: Cystic Fibrosis
Kitabis Pak (tobramycin) is an aminoglycoside inhalation solution co-packaged with a
PARI LC PLUS® Reusable Nebulizer for the management of cystic fibrosis

Xigduo XR(dapagliflozin and metformin
hydrochloride) Extended-Release Tablets
Company: AstraZeneca
Date of Approval: October 30, 2014
Treatment for: Diabetes Type 2
Xigduo XR (dapagliflozin and metformin hydrochloride)
is a once-daily sodium-glucose cotransporter 2 (SGLT2)
inhibitor and biguanide combination for the treatment
of type 2 diabetes.

Sotylize
(sotalol hydrochloride) Oral Solution
Company: Arbor Pharmaceuticals
Date of Approval: October 22, 2014
Treatment for: Ventricular Arrhythmia,
Atrial Fibrillation, Atrial Flutter
Sotylize (sotalol hydrochloride) is an antiarrhythmic
indicated for the treatment of ventricular arrhythmias
and the maintenance of normal sinus rhythm in
patients with history of highly symptomatic atrial
fibrillation/flutter

Long-acting beta agonist olodaterol for use
in COPD
(August 2014)
Olodaterol, a once-daily, long-acting beta agonist (LABA),
is approved for the treatment of COPD in the United
States, Canada, Russia, Denmark, and several other
countries; it is not approved for use in asthma.
In two trials that included a total of 1838 subjects with
moderate-to-severe COPD, 24 weeks of olodaterol
resulted in significant improvement in airflow limitation
and quality of life, compared with placebo .

Long-acting beta agonist
Olodaterol
for use in COPD
(August 2014)
Similar results were seen in a separate pair of trials that
included a total of 1266 subjects and lasted 48 weeks . In
all reports, adverse events with olodaterol were
comparable to those of placebo

Bronchoscopic lung volume reduction
with
Nitinol coils
in severe emphysema
(October 2014)
Bronchoscopic placement of nitinol coils is an
experimental method to treat emphysema. When the
coils are deployed in areas of emphysema, they resume
their coiled shape, collecting and collapsing the
surrounding lung tissue and thereby reducing
hyperinflation.

with
Nitinol coils
in severe emphysema
In a multicenter, observational study, 60 patients with
severe heterogeneous emphysema underwent
bronchoscopic placement of nitinol coils (55 bilateral, 5
unilateral) with a median of 10 coils per lobe .
Serious adverse events included seven COPD
exacerbations, four pneumothoraces, and one
episode of hemoptysis.

with
Nitinol coils
in severe emphysema
The remaining patients experienced modest but
sustained improvements in quality of life and lung
function at six and 12 months. Randomized trials with a
longer duration of follow-up are needed to confirm
these findings.

Statin
Therapy does not reduce COPD
exacerbations
(June 2014)
In observational studies of chronic obstructive
pulmonary disease (COPD), statins have been associated
with a reduced rate and severity of exacerbations, rate
of hospitalizations, and mortality.

Statin
Therapy does not reduce COPD exacerbations
(June 2014)
However, these beneficial effects were not supported in
a trial that randomly assigned 885 participants with
COPD, but without other indications or contraindications
for statin therapy, to simvastatin or placebo for up to 36
months .
Simvastatin did not reduce the rate of exacerbations or
the time to first exacerbation

Prophylactic antibiotics
Do not benefit patients with acute liver
failure
(October 2014)
The role of prophylactic antibiotics in the treatment of
patients with acute liver failure is controversial.
In a retrospective study of 1551 patients with acute
liver failure, antimicrobial prophylaxis did not reduce
the incidence of bloodstream infection or mortality .

Antibiotic decontamination of the
digestive tract in the ICU and
antimicrobial resistance
(October 2014)
The use of prophylactic antibiotics to decontaminate the
oropharyngeal and/or digestive tracts of critically ill
patients and reduce the risk of infection confers a
modest mortality benefit but is not widely used, in part,
because of concern that it can promote antimicrobial
resistance.

(October 2014)
A large multicenter cluster-randomized trial in intensive
care units in the Netherlands compared resistance rates
with selective oropharyngeal decontamination (SOD;
antibiotics applied to the oropharynx only) and selective
digestive decontamination (SDD; antibiotics applied to
the oropharynx and through a nasogastric tube plus a
different intravenous antibiotic).

(October 2014)
Rates of rectal colonization with highly resistant bacteria
were overall lower with SDD than SOD, but colonization
with aminoglycoside-resistant gram-negative bacilli
increased more over time with SDD than SOD.

(October 2014)
Given the very low baseline rate of antimicrobial
resistance in the Netherlands and the absence of a
control group that received no prophylactic antibiotics,
these findings do not sufficiently allay concerns about
long-term antimicrobial resistance with antibiotic use for
decontamination of the gastrointestinal tract.

Restrictive transfusion threshold safe in
septic shock
(October 2014)
Blood transfusion using a lower (restrictive)
hemoglobin threshold has been adopted in a variety of
settings, including hemodynamically stable patients in
the intensive care unit.
However, debate has remained regarding the safety of
this approach in patients with septic shock.

septic shock
(October 2014)
A new randomized trial has shown that a restrictive
hemoglobin threshold of 7 g/dL can be used in this
setting. The Transfusion Requirements in Septic Shock
(TRISS) trial randomly assigned 998 patients with
septic shock to a restrictive or a liberal transfusion
strategy (hemoglobin threshold of 7 or 9 g/dL) .

septic shock
(October 2014)
All outcomes were similar between the two groups at
90 days, including mortality, cardiac ischemia, and
transfusion reactions.
We and other experts agree that for most patients with
septic shock, red blood cell transfusion should be
reserved for those with a hemoglobin of ≤7 g/dL.

Enteral versus parenteral nutrition in
critically ill patients
(October 2014)
In critically ill patients, the benefits of enteral nutrition
compared with parenteral nutrition are unclear, with
small randomized trials suggesting marginal benefit to
enteral nutrition in surgical patients.
One large multicenter randomized trial compared
enteral nutrition with parenteral nutrition in 2400
critically ill patients, most of whom had medical rather
than surgical illnesses .

Enteral versus parenteral nutrition in
(October 2014)
There was no difference in mortality or rates of
infections between the groups. These findings support
the continued use of enteral nutrition in both medical
and surgical patients who are critically ill, when feasible.

Immune modulatory enteral feeds in
(August 2014)
Small retrospective studies have suggested that high-
protein enteral formulas with immune modulating
nutrients (IMHP), such as glutamine, selenium, and
omega-3 fatty acids, may improve survival and reduce
the rate of infections in critically ill patients.
The effect of IMHP was examined in a multicenter,
randomized, double-blind trial of 301 mechanically
ventilated adult patients (MetaPlus) .

(August 2014)
There was no difference reported in the rate of
infections, duration of mechanical ventilation, or length
of ICU or hospital stay.
Use of IMHP was associated with a higher six-month
mortality rate (54 versus 35 percent) in one predefined
subpopulation of medical patients, which was not seen
in the surgical or trauma patients.

(August 2014)
These findings are consistent with previous large
randomized trials of high-protein formulas
supplemented with glutamine or omega-3 fatty acids
alone, which also found lack of benefit and possible
harmful effects.

Palliative care of patients in the intensive
care unit
(July 2014)
The traditional goals of intensive care unit (ICU) care
are to reduce the morbidity and mortality associated
with critical illness, maintain organ function, and
restore health.
When the acute illness or accompanying organ
dysfunction is refractory to treatment, these goals of
care can no longer be met.

care unit
(July 2014)
When aggressive care is likely to result in outcomes
that are not congruent with patient values and
preferences, ICU clinicians must ensure that patients
die with dignity.

care unit
(July 2014)
A paradigm to assist in the delivery of palliative care to
patients dying in the ICU has been developed that is
termed the “ABCDs (attitudes, behaviors, compassion,
and dialogue) of dignity-conserving care” .
Practical preparatory procedures to ensure patient
comfort and dignity before withdrawal of life support
are also available

Intraoperative PEEP
(June 2014)
The optimal level of intraoperative positive end-
expiratory pressure (PEEP) for mechanically ventilated
patients undergoing surgery is unknown.
In the PROVHILO trial, 900 patients undergoing
abdominal surgery and at moderate risk of pulmonary
complications were randomly assigned to receive
either high levels (12 cm H2O) or low levels (≤2 cm
H2O) of PEEP, administered at a constant tidal volume
of 8 mL/kg .

Intraoperative PEEP
(June 2014)
The rate of postoperative complications, length of ICU
stay, and mortality were no different between the
groups.
However, patients on high levels of PEEP were more
likely to become hypotensive (46 versus 36 percent)
and require vasopressor support (62 versus 52
percent).

Intraoperative PEEP
(June 2014)
High levels of PEEP intraoperatively do not appear to
be of benefit and may be harmful in patients
undergoing abdominal surgery, although the level of
PEEP used in this study (12 cm H2O) was unusually
high, which may have mitigated any potential benefit.
Further studies are needed before an optimal level of
PEEP can be recommended in this population.

NEW ANTIBIOTICS
2014
• SAMIR EL ANSARY
Critical Care Antibiotics

INTERSTITIAL LUNG DISEASE
Autologous hematopoietic stem cell
therapy in systemic sclerosis
(July 2014)
In the Autologous Stem cell Transplantation
International Scleroderma (ASTIS) trial, a total of 156
patients with early diffuse cutaneous systemic sclerosis
(dcSSc) were randomly assigned to receive either
hematopoietic stem cell transplant (HSCT) or 12
monthly pulses of intravenous cyclophosphamide .

(July 2014)
The primary end point was event-free survival, defined
as the time until death due to any cause or the
development of persistent major organ failure.
The study found that HSCT resulted in worse early, but
better long-term, event-free and overall survival.

(July 2014)
HSCT was associated with significant improvements in
lung function, skin softness, functional ability, and
quality of life, but also with more viral infections and
reduced renal function.

(July 2014)
Patients who have severe skin disease with or without
moderate (but not severe) internal organ involvement,
and who continue to have progressive disease despite
an initial trial of immunosuppression, should be
referred for further evaluation to specialized centers
with expertise performing HSCT for scleroderma.

(July 2014)
(See "Immunomodulatory and antifibrotic approaches
to the treatment of systemic sclerosis (scleroderma)",
section on 'Autologous stem cell transplantation'.)

LUNG CANCER
Combination chemotherapy for patients with a late
relapse of small cell lung cancer
(June 2014)
Treatment of patients with relapsed small cell lung
cancer is a difficult problem that is usually managed
with single agent chemotherapy.
In a randomized phase III trial in patients with a
sensitive relapse (ie, more than 90 days after
completion of their initial combination chemotherapy),
treatment with a platinum-based combination regimen
significantly increased overall and progression-free
survival .

LUNG CANCER
Combination chemotherapy for patients with a late
relapse of small cell lung cancer
(June 2014)
However, severe hematologic toxicity was increased. For
patients with a sensitive relapse, treatment with the
original platinum-based combination or a novel
platinum-based combination can be considered. (See
"Treatment of refractory and relapsed small cell lung
cancer", section on 'Combination chemotherapy'.)

Novel anticoagulant strategies with
potentially lower bleeding risk
(December 2014)
Anticoagulants reduce the risk of thromboembolism,
but this benefit is balanced by an increased risk of
bleeding.
Two new strategies for anticoagulation are in
development that may carry a lower risk of bleeding
compared with currently available agents.

(December 2014)
The first uses an antisense oligonucleotide to reduce
production of coagulation factor XI (FXI-ASO).
In patients undergoing knee replacement, treatment
with FXI-ASO was associated with a 3 percent risk of
venous thromboembolism, compared with
approximately 30 percent with low molecular weight
heparin, without increasing bleeding .

(December 2014)
However, the duration of anticoagulation was long,
injection site reactions were common, and no antidote
is available.

(December 2014)
The second strategy targets polyphosphate, a pro-
thrombotic substance released from activated platelets
or microbes .
In preclinical models, polyphosphate inhibitors have
shown reduced arterial thrombosis without increased
bleeding.
Additional studies are awaited to determine the role of
these new strategies in clinical practice.

Mortality benefit for thrombolysis in
patients with acute pulmonary embolus
(June 2014)
Thrombolytic therapy is of uncertain benefit in patients
with pulmonary embolus (PE).
A meta-analysis of 16 trials reported that, compared to
anticoagulation alone, thrombolytic therapy was
associated with a lower all-cause mortality (2.2 versus
3.9 percent) and a reduced rate of recurrent
thromboembolism (1.2 versus 3.0 percent).

(June 2014)
However, it increased the risk of major hemorrhage
(9.2 versus 3.4 percent) including intracranial
hemorrhage (1.5 versus 0.2 percent).
No mortality benefit was reported in older patients
(>65 years), a population in whom the risk of
hemorrhage was greatest.

(June 2014)
The data were not robust for any one specific patient
population, nor was the optimal agent, dose, or
method of delivery identified. Thus, the routine
administration of thrombolytic therapy for patients
with PE remains questionable and the decision to
administer it should continue to be made on an
individual patient basis.

CPAP therapy for older adults with
obstructive sleep apnea
(October 2014)
Continuous positive airway pressure (CPAP) is the
mainstay of therapy for most adults with obstructive
sleep apnea (OSA), but previous clinical trials have
enrolled primarily younger adults.

(October 2014)
In a multicenter trial that included 278 adults ≥65
years of age with newly diagnosed OSA, patients
randomized to receive CPAP therapy plus best
supportive care had improvement in daytime
sleepiness compared with those assigned to best
supportive care alone .

(October 2014)
The benefits of CPAP were present at both three- and
12-month time points and were greater in those with
higher CPAP usage and higher baseline sleepiness
scores. Secondary endpoints, including quality of life,
mobility, cognitive function, and cardiovascular
events, were similar between groups

Orexin receptor antagonist suvorexant for
treatment of insomnia
(August 2014)
The first dual orexin receptor antagonist, suvorexant
(Belsomra), has been approved by the US Food and
Drug Administration for the treatment of insomnia but
is not yet available for clinical use.
Orexin is a hypothalamic neuropeptide that plays a key
role in regulating wakefulness and the sleep-wake
cycle.

(August 2014)
In clinical trials for up to one year, suvorexant was
associated with improved subjective total sleep time
and time to sleep onset compared with placebo .
The most common adverse effect is somnolence, and
next-day driving impairment has been seen in both
men and women at the maximum approved dose (20
mg).

(August 2014)
The role for this novel medication, which is expected to
be a C-IV controlled substance, remains to be
determined, as suvorexant has not yet been compared
with other pharmacologic or behavioral therapies for
insomnia

Lower risk of fatal bleeding with target
specific oral anticoagulants versus warfarin
(November 2014)
All anticoagulants carry a risk of bleeding, and the lack
of an antidote for direct factor Xa inhibitors
(rivaroxaban, apixaban, edoxaban) and the direct
thrombin inhibitor dabigatran increases concerns
about this risk.

(November 2014)
Reassuringly, a meta-analysis of 12 randomized trials in
patients with atrial fibrillation or venous
thromboembolism that compared bleeding risk with
these agents versus vitamin K antagonists found lower
rates of fatal bleeding, major bleeding, and intracranial
bleeding with the direct factor Xa and direct thrombin
inhibitors

(November 2014)
Individual patient factors continue to play a role in
anticoagulant choice and the development of reversal
agents for the factor Xa and thrombin inhibitors is
underway.

Investigational agent for reversal of
multiple anticoagulants
(November 2014)
Reversal agents for the target specific oral
anticoagulants are lacking.
In a study of 80 healthy volunteers given a therapeutic
dose of the direct factor Xa inhibitor edoxaban, a
reversal agent under development (PER977)
normalized the whole blood clotting time within 10
minutes; in contrast, normalization of the clotting time
took 12 to 15 hours in individuals given edoxaban
followed by placebo .

Investigational agent for reversal of
multiple anticoagulants
(November 2014)
Agents for the target specific oral anticoagulants are
lacking.
In addition to binding direct factor Xa inhibitors,
PER977 also binds the direct thrombin inhibitor
dabigatran, as well as unfractionated and low
molecular weight heparins.

Infection prevention measures for
cystic fibrosis
(October 2014)
Evidence is accumulating that a variety of
respiratory pathogens can be transmitted among
individuals with cystic fibrosis (CF) within the
health care system.
In particular, highly transmissible strains of
Pseudomonas aeruginosa have been reported.

cystic fibrosis
(October 2014)
Compared with sporadic strains of P. aeruginosa,
infection with highly transmissible strains is
associated with increased need for health care
and antibiotics.
To minimize risk of transmission, the CF
Foundation has published updated guidelines for
infection prevention and control to be applied to
all individuals with CF, regardless of respiratory
tract culture results .

cystic fibrosis
(October 2014)
The guidelines include the following measures:
●Clinicians should use contact precautions
(gown and surgical masks) at all times when
caring for patients with CF.
●Patients with CF should wear surgical masks in
the health care setting.

cystic fibrosis
(October 2014)
The guidelines include the following measures:
●Patients with CF should not congregate within
or outside of the health care setting, should
remain at least six feet away from other patients
with CF, and be cared for in single-patient rooms
when they require admission

Ivacaftor for cystic fibrosis (August 2014)
Ivacaftor is a drug that restores function of the
mutant ion channel in patients with cystic fibrosis
(CF) due to a G551D mutation.
In initial randomized trials, beneficial effects of
ivacaftor significantly exceeded those of any other CF
treatments.
Now, a multicenter longitudinal study demonstrates
improvements in pulmonary function and weight
gain, reduced hospitalization, and decreased
Pseudomonas aeruginosa colonization— all within
six months of initiation .

Ivacaftor for cystic fibrosis
(August 2014)
Ivacaftor is a drug that restores function of the
mutant ion channel in patients with cystic fibrosis
(CF) due to a G551D mutation.
These findings further establish the
importance of ivacaftor in the treatment
of CF due to G551D or other “gating”
mutations.

Cardiovascular outcomes and azithromycin
use for pneumonia
(June 2014)
Large observational studies have shown conflicting
results with regards to a possible increase in
cardiovascular mortality associated with azithromycin
use.
A more recent large cohort study evaluated the
association between azithromycin use and all-cause
mortality and cardiovascular events in more than 60,000
United States veterans ≥65 years of age who were
hospitalized with pneumonia .

use for pneumonia
(June 2014)
Ninety-day mortality was significantly lower in those
who were treated with an azithromycin-containing
regimen versus those who received other guideline-
concordant antibiotics.
Compared with patients who did not receive
azithromycin, those who received azithromycin were
slightly more likely to have a myocardial infarction, but
not arrhythmias, heart failure, or any cardiac event.

use for pneumonia
(June 2014)
An analysis of these data suggested that seven deaths
were averted for each non-fatal myocardial infarction
associated with azithromycin use, reflecting a net
benefit of azithromycin for patients ≥65 years of age
with pneumonia. (See "Azithromycin, clarithromycin,
and telithromycin", section on 'QT interval prolongation
and cardiovascular events'.)

GOOD LUCK
SAMIR EL ANSARY
ICU PROFESSOR
AIN SHAMS
CAIRO
elansarysamir@yahoo.com

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