Daptomycin 8mg/day in a single dose for severe Staph infections

Sepsis Cure
Rate With Daptomycin Up to 85%

Becky
McCall

April
11, 2012 (London, United Kingdom) — Daptomycin (Cubicin, Novartis)
achieves clinical cure rates of 72% in sepsis caused by Staphylococcus
aureus and of 85% in sepsis caused by Staphylococcus epidermidis.
High-dose daptomycin is also safe and tolerable, according to posters presented
here at the 22nd European Congress of Clinical Microbiology and Infectious
Diseases.

Pascal
Dohmen, MD, PhD, a cardiac surgeon at the Heart Centre Leipzig in Germany,
presented the study on daptomycin in sepsis, which he led. He also discussed 2
other posters in the series; all used data from the European Cubicin Outcomes
Registry and Experience (EU-CORE) database, a retrospective, multicenter, noninterventional
registry.

"Even in
patients with severe sepsis and septic shock, outcomes were very good. We would
normally see 40% to 50% mortality, but here we see an overall clinical success
rate of 71%, and nearly 80% in endocarditis," Dr. Dohmen
told Medscape Medical News.

"As
a surgeon, I sometimes find myself standing with my back against a wall because
mortality in endocarditis, especially
in prosthesis endocarditis, can rise to 30% to 40%," he explained.

For
the analysis of daptomycin in sepsis, data were collected from 2006 to 2011.
Demographic and clinical data were drawn from patients in Europe, Russia, Latin
America, and India. For study inclusion, patients had to have sepsis as the
primary infection, had to have received at least 1 dose of daptomycin, and had
to have had more than 30 days of follow-up.

All
302 patients who met the inclusion criteria had significant underlying disease,
most commonly cardiovascular (55%) and renal disease (23.8%).

For
the initial dose of daptomycin, 53.3% of patients received 6 mg/kg, 17.2%
received 4 mg/kg, and 12.9% received more than 8 mg/kg. The median duration of
treatment was 10 days. Dr. Dohmen reported that 80% of patients had previously
received another antibiotic.

"We
know that mortality in sepsis is high. Twenty percent of patients were older
than 75 years, almost 20% were on dialysis, and many had comorbidities,"
said Dr. Dohmen. "Primary infections included 31% S aureus, 50% of
which were MRSA [methicillin-resistant S aureus]-positive. Enterococci
were found in 17% of patients, and 20% were culture negative."

Assessments
were based on clinical success, defined as cure or improvement. Cure entailed a
resolution of clinical signs and symptoms, no additional antibiotic, and
negative culture at the end of therapy. Improvement entailed partial resolution
of signs and symptoms or a de-escalation of therapy.

The
overall clinical success rate with daptomycin in patients with sepsis was 71%
(43% cured and 28% improved); the clinical failure rate was 12%, and 18% of cases
were nonevaluable. In endocarditis, 79% of patients achieved clinical success.

Dr.
Dohmen explained that he found daptomycin to be a real benefit to his patients
with endocarditis.

"These
patients have severe disease and poor survival, so the combination of surgical
treatment plus a high dose of daptomycin and other antibiotics is usually
effective," he continued. "There is a rapid bactericidal effect,
which is essential for patients with surgical-site infections or endocarditis.
Within 3 days, you can see results in lab tests and clinically."

In
coagulase-negative staphylococci, 84% of patients achieved clinical cure. "We see
coagulase-negative staphylococci often. We also find that MRSA and MSSA
[methicillin-susceptible S aureus] have almost identical success
rates. These rates are superior to vancomycin," noted Dr. Dohmen.

The
median time to improvement was 4 days in patients with sepsis, and the clinical
success rate was 73.7% and 70.7% when used as first-line and second-line
therapy, respectively.

By
dose, patients receiving 6 mg/kg had a 78% clinical success rate; with the
higher dose of at least 8 mg/kg, a clinical success rate of 74% was achieved.
"We see a slightly lower success rate because these patients have very
severe disease," Dr. Dohmen explained.

Safety
and tolerance were excellent, with 3% of patients experiencing adverse or
severe adverse events. "At high doses, we did not see an increase in
adverse events or serious adverse events, even after 30 days," added Dr.
Dohmen.

The
other posters that Dr. Dohmen discussed were related to the use of higher-dose
daptomycin (8 mg/kg) and outpatient treatment with daptomycin.

In
EU-CORE, patients given daptomycin 8 mg/kg were treated for a median of 25
days.

Previously,
there were tolerability issues related to "a higher dose of daptomycin
when given twice a day. If it is given once
a day at a dose of 8 mg/kg per day, these issues are no longer cause
for concern," said Dr. Dohmen.

Daptomycin
4 mg/kg once daily
is approved for adult patients in the United States and the European Union for
the treatment of complex skin and soft tissue infection caused by Gram-positive
bacteria. Daptomycin 6 mg/kg once
daily is approved for bacteremia, including right-sided endocarditis due to S
aureus. However, evidence of favorable outcomes with
high-dose daptomycin (at least 8 mg/kg) in infections with high morbidity and
mortality has resulted in its inclusion in recent national and international
treatment guidelines in Europe and in the United States.

By
primary infecting pathogen, clinical success rates with high-dose daptomycin
were 92.4% for coagulase-negative staphylococci, 88.9% for S aureus (88.4%
for MRSA and 88% for MSSA), and 89.3% for Enterococci-related
infections.

High-dose daptomycin
was found to be as safe as the conventional approved doses (4 and 6 mg/kg once
a day).

A
third poster presented data on the use of daptomycin in outpatients with
serious Gram-positive infections. Daptomycin was given as a simple
intravenous (IV) injection at an outpatient visit. "Most antibiotics
require a longer period of time and patients need to remain in the
hospital," explained Dr. Dohmen.

"With
this IV administration, patients can be treated as outpatients, which improves
their quality of life. If patients have MRSA, they usually have to stay
isolated in a room, which can be distressing for them."

He
added that the outpatient scenario reduced hospital costs and the risk of
patients developing hospital-acquired infections.

Andras
Farkas, PharmD, clinical assistant professor of pharmacy practice at Nyack
Hospital in New York, said that daptomycin is used for right-sided
endocarditis, skin and soft tissue infections, and bacteremia in the United
States.

"Some
believe it is a miracle drug, but I'm not too sure at this point," he noted.
"Vancomycin is an agent that has been used as the standard of care, so we
use daptomycin when vancomycin has failed."

He
added that recent evidence has suggested that alternative agents, such as
daptomycin, can be used for serious infections caused by S aureus in
patients with elevated vancomycin MICs [minimum inhibitory concentrations].
"When dealing with isolates having a MIC greater than 1 µg/mL, the
coverage with vancomycin is very unlikely to achieve the desired
pharmacodynamic target."

He
is impressed by the analysis on the use of high-dose daptomycin. "The
European Union guidelines and the Infectious Diseases Society of America both
recommend increasing the dose of daptomycin in certain situations. Most clinicians use 8 to 10 mg/kg of daptomycin,
but there are no well-designed clinical trials to support these doses."

"This
poster is from registry data, but it shows the drug is relatively safe and that
higher doses do not seem to cause increased rates of musculoskeletal-related
adverse events," he concluded.

These
studies were funded by Novartis. Dr. Dohmen reports receiving research grants
from Novartis. Dr. Farkas has disclosed no relevant financial relationships.

22nd
European Congress of Clinical Microbiology and Infectious Diseases (ECCMID):
Posters 1844, 1845, and 1846. Presented April 2, 2012.