<?=>J?D=J>;D;L;H#;D:?D=87JJB;7=7?DIJ7DJ?C?9HE8?7BH;I?IJ7D9; HWf_Zbo_dYh[Wi_d]Wdj_c_YheX_Wbh[i_ijWdY[_ied[e\j^[ceiji[h_ekiYb_d_YWbc_YheX_ebe]_YfheXb[ci\WY_d]c[Z_Y_d[Ij[l[d@$CWhj_d"F^Whc:"<99C jeZWo$M_j^iecWdofWj_[dji_dj^[_dj[di_l[YWh[kd_j ?9K Wjh_ia\ehXWYj[h_WbWdZ\kd]Wb_d\[Yj_edi"ijhWj[]_[ijeFWc[bW7$B_fi[jj"C:"<99CYecXWjWdj_c_YheX_Wbh[i_ijWdY[WdZ[\\[Yj_l[bojh[Wj_d\[Yj_edWh[e\]h[Wj_cfehjWdY[$H[ZkY_d]7dj_c_YheX_WbH[i_ijWdY[_dj^[?9K
“In truth, we really can’t prevent antimicrobial resistance. Rather,
handle that,” Kollef said. “New technologies are being developed
it’s something we need to try to control,” stated Marin H. Kollef,
to provide rapid microbiologic evaluation, but until they become
MD, from Washington University in St. Louis, Missouri. One key
available we still have to treat infections broadly. De-escalation is
to controlling resistance is to look at antimicrobial treatment in the
one tool we can use to try to minimize resistance.” Examples of
ICU as a balancing act. “On one hand, we need to think about
de-escalation in the treatment of ventilator-acquired pneumonia
appropriately treating patients,” Kollef said. “On the other hand,
(VAP) have been reported in the literature (Rello et al. Crit Care Med.
we always need to be thinking about avoiding unnecessary antimi-
2004;32:2183; Leone et al. Crit Care Med. 2007;35:379). De-escala-
tion, which involves narrowing the therapy once microbiologic
Antimicrobial resistance is of great concern because of its asso-
results are obtained, also enables the clinician to use the shortest
ciated increase in morbidity, mortality, and healthcare costs–and
course of therapy that is clinically adequate for the infection.
because fewer effective antimicrobial agents are available today.
Duration of antimicrobial therapy is of concern in terms of
One example of ineffective agents can be seen in the quinolone
efficacy and potential for resistance. Investigators have reported
class. According to a study reported in 2003, increases in fluoro-
that longer (15 days vs. 8 days) antimicrobial therapy for VAP had
quinolone use paralleled increases in resistance rates in Pseudomonas
no impact on survival (Chastre et al. JAMA. 2003;290:2588). Other
aeruginosa and gram-negative bacilli infections from 1990 to 2000
researchers examined the occurrence of unnecessarily prolonged
(Neuhauser et al. JAMA. 2003;289:885). “Part of the reason for
antibiotic use in the ICU and found that 50% of patients who had
this may have been some underdosing of quinolones,” noted Kollef,
no evidence of infection were still receiving
“particularly for infections in the lung, where you might not get
antimicrobial therapy one week later (Aarts
et al. Intensive Care Med. 2007;33:1369). JWXb['$'(Ij[fijeFh[l[dj7dj_c_YheX_Wb
The link between more frequent use of an antimicrobial agent
H[i_ijWdY[7ced]>eif_jWb_p[Z7Zkbji
and increased resistance, and hence, increased mortality, is well
minimizing antimicrobial resistance. “You
known. “We also know that the resistance mechanisms involve
Fh[l[dj?d\[Yj_ed
beta-lactamases and multiple efflux pumps,” he said. “Whether we
with the right dose,” he said. He cited an
like it or not, accumulation of extended-spectrum beta-lactamases
investigation of four dosing regimens of
Ij[f(0 H[cel[YWj^[j[hiWiieedWifeii_Xb[
(ESBLs), AmpC beta-lactamases, and fluoroquinolone resistance
is driving more use of carbapenem.” The consequence of that is
dose (2 g every 8 hours over a 3-hour infu-
:_W]dei[WdZJh[Wj?d\[Yj_ed;\\[Yj_l[bo
sion) gave the greatest likelihood of appro-
The incidence of sepsis in the United States has been rising
priately treating P aeruginosa and minimiz-
and is expected to continue to climb over the next few decades
ing the emergence of resistance (Santos et
(Angus et al. Crit Care Med. 2001;29:1303). “Thus, we’ll see the
al. Clin Microbiol Infect. 2007;13:579).
need for increased antimicrobial use and more problems with resis-
Ki[7dj_c_YheX_WbiM_i[bo
tance,” said Kollef. Using the appropriate agent initially is crucial,
involve treating the infection, not the con-
he noted, citing data that revealed increased mortality when inap-
propriate initial antimicrobial therapy was administered (Ibrahim et
Ij[f-0 Jh[Wj_d\[Yj_ed"dejYedjWc_dWj_ed
bronchoalveolar lavage (BAL). Ibrahim et
Ij[f.0 Jh[Wj_d\[Yj_ed"dejYebed_pWj_ed
Illustrating the importance of appropriate initial therapy,
al described the results of a protocol for
Ij[f/0 Ademm^[djeiWodejelWdYecoY_d
Kollef described a study involving patients who presented to the
emergency department (ED) with septic shock (Micek et al. Crit Care
suspected VAP (Ibrahim et al. Crit Care
Ij[f'&0 IjefWdj_c_YheX_Wbjh[Wjc[djm^[dYkh[Z
Med. 2006;34:2707). Computer-based algorithms indicating appro-
Med. 2001;29:1109). All were treated with
priate antimicrobial treatment for patients with septic shock were
combination antimicrobial therapy, based
Fh[l[djJhWdic_ii_ed
developed for ED staff. Most patients received combination therapy
on the unit-specific antibiogram. “The
consisting of three antibiotic agents. The ED-based sepsis protocol
key part was de-escalation,” said Kollef.
was associated with reductions in mortality, decreasing from 48.3%
to 30% (p=.04), length of stay, and costs. No new antimicrobial
based on the culture results, and was lim-
9[dj[hi\eh:_i[Wi[9edjhebWdZFh[l[dj_ed 9:9
resistance occurred among these patients, and they were more likely
ited to 7 days. Importantly, the protocol
to be treated with an appropriate initial regimen compared with
reduced the duration of treatment in the
patients who were treated before the algorithms were instituted.
The Centers for Disease Control and Prevention (CDC) pro-
In closing, Kollef contrasted the old and new paradigm of anti-
vides a 12-step approach to preventing antimicrobial resistance
microbial treatment. The old paradigm advocated starting therapy
among hospitalized adults (see Table 1). One step involves cath-
with narrow-spectrum agents, such as penicillin, and using the effi-
eters. “Removing catheters as soon as possible is critical because
cient low dose, which also may be associated with fewer adverse
that's where biofilm forms and where resistance can emerge,”
effects. Duration of therapy under the old paradigm was long: at
Kollef said. Prevention programs are effective in educating ICU
least 2 weeks. “With the new paradigm, you want to get it right the
nurses and physicians on maintenance of catheters, hand-washing,
first time and follow an aggressive de-escalation approach,” Kollef
proper attire during catheter placement, sterilization technique,
explained. “That means hitting the organism hard up front. You also
proper barrier precautions, and other procedures that will mini-
want to avoid low doses, which promote resistance. It’s important to
mize the rate of catheter-related infections.
optimize the dosing; our pharmacy colleagues can guide us. In terms
The CDC also recommends targeting pathogens and using
of duration, seldom do we need to push therapy beyond 7 days.”
local data. "De-escalation and local surveillance are the ways to
CE credit at www.sccm.org/CongressReview08
JUNE 2008 CWdW][c[dje\Ckbj_fb[:hk]#H[i_ijWdY[8WYj[h_Wb?d\[Yj_edi
New antimicrobial agents are on the horizon that target mul-
escens, Moraxella catarrhalis, Morganella morganii, Neisseria gonorrhoeae, and
tiple-drug resistant infections, which include methicillin-resistance
N meningitidis. Colistin and polymyxin B show no activity against the
Staphylococcus aureus (MRSA), P aeruginosa, Acinetobacter species, and
other gram-negative organisms. In addition, one compound that
Colistin and polymyxin often are used with other drugs in
has been around for a while shows promise in combating multiple-
combination therapy. Limited data suggest a synergistic bacteri-
drug resistant infections, according to Steven J. Martin, PharmD,
cidal effect in vitro is achieved when colistin is used with rifampin
FCCM, from the University of Toledo College of Pharmacy.
or ceftazidime, particularly against P aeruginosa (Sarkar. Am J
Newer agents showing efficacy against MRSA include dalba-
Health Syst Pharm. 2007;64:2462; Zavascki. J Antimicrob Chemother.
vancin, oritavancin, telavancin, daptomycin, linezolid, tigecycline,
and ceftobiprole. In the treatment of gram-negative organisms,
Clinical data focus on case reports on the use of colistin in the
effective newer agents include doripenem, ceftobiprole, and tige-
treatment of P aeruginosa, Acinetobacter baumannii, E coli, and K pneu-
cycline, and colistin, which is the oldest of these drugs. Martin
moniae (Sarkar. Am J Health Syst Pharm. 2007;64:2462). “Although
there are limited data in the literature on the microbiologic response observed with this drug in multidrug-resistant infections, empirically
Doripenem. Doripenem, a new carbapenem, has a similar bacteri-
colistin therapy appears to be a sound idea,” Martin noted.
cidal spectrum to that of imipenem and meropenem. It has broad
Use of colistin fell out of favor in the 1960s due to its neph-
activity against most gram-negative rods, most gram-positive cocci,
rotoxic properties. In case reports of 199 critically ill patients who
and most anaerobes. Binding to bacterial membranes, doripenem
were treated with colistin for multidrug-resistant infections, nephro-
demonstrates similar or somewhat better potency against P aerugino-
toxicity was observed in 52 (26%) patients (Sarkar. Am J Health Syst sa compared with imipenem or meropenem. Doripenem also exerts
Pharm. 2007;64:2462). Colistin also has neurotoxic properties as a
strong activity against Acinetobacter species, Enterobacteraerogenes,
neuromuscular blocking agent, but a neurotoxic effect may be dif-
ESBL-producing organisms (Escherichia coli, Klebsiella pneumoniae),
ficult to detect in sedated or critically ill patients.
and many other gram-negative rod organisms. In terms of activity
The dosing, pharmacokinetics, and pharmacodynamics of
against gram-positive cocci, doripenem is not effective in treating
colistin have not been studied well. More work has been reported on
MRSA, but it does demonstrate efficacy against pneumococci, par-
the use of colistin in patients with cystic fibrosis than in the critically
ticularly penicillin-resistant pneumococcus. Current indications for
ill population, leaving the door open to future research in this area.
doripenem include intra-abdominal infection, urinary tract infec-tion, and pyelonephritis.
Dalbavancin. Dalbavancin is a second-generation glycopeptide that
Doripenem has a relatively short (1 h) half-life, as do other car-
received recent Food and Drug Administration (FDA) approval.
bapenems, and is administered every 8 hours. “Infusion time and the
Like vancomycin, it has broad gram-positive activity, which includes
pharmacodynamic properties of this drug can be put to advanta-
MRSA, penicillin-resistant Streptococcus pneumoniae and vancomy-
geous use,” said Martin. Doripenem undergoes renal elimination.
cin-resistant enterococci (VRE). Unlike vancomycin, dalbavancin
Recent data from two international multicenter trials show the
has a very long half-life (170-210 h). “Thus, dalbavancin allows
efficacy of doripenem in the treatment of nosocomial pneumonia
once-weekly dosing, which is an interesting concept,” Martin
(Ortho-McNeil, Inc. Data on file; 2007.) In one study, patients with
stated. “Dalbavancin provides a long period of time in which
early onset VAP were randomized to receive doripenem 500 mg
the concentration is above the MIC for most MRSA organisms.”
every 8 hours or piperacillin/tazobactam 4.5 g every 6 hours. The
Approximately 40% of the intact drug is eliminated renally, and up
infusion time for the doripenem dose was short (30 min). When
to 50% is excreted into the feces. Dalbavancin does not appear to
Pseudomonas or MRSA infections were suspected, adjuvant therapy
produce any significant adverse effects.
consisting of amikacin (80%)/vancomycin (15%) was instituted.
Microbiologic data indicate that dalbavancin possesses slightly
“Although the overall clinical cure rates were similar in patients who
more potent MICs against methicillin-sensitive S aureus (MSSA)
did not have P aeruginosa infection, differences in clinical cure rates
than vancomycin and greater potency against MRSA infections
were observed for the two therapies among patients with P aerugi-
than vancomycin, linezolid, or daptomycin (Chen. Int J Clin Pract.
nosa–83% for doripenem versus 71% for piperacillin,” he said.
2007;61:853). When studied in complicated skin and skin struc-
The second study compared doripenem 500 mg every 8 hours
ture infections, dalbavancin and linezolid had similar cure rates
over a prolonged (4-hour) infusion with imipenem 500 mg every
(Jauregui. Clin Infect Dis. 2005;41:1407). In an open-label multi-
6 hours in patients with early/late VAP. “Once again, dramatic
center trial comparing dalbavancin and vancomycin in the treat-
differences favoring doripenem were seen in patients who had P
ment of catheter-related bacteremia, the success rates were 87%
aeruginosa infection. Clinical cure rates were 65% with doripenem
and 50% for dalbavancin and vancomycin, respectively.
and 35% with imipenem,” he reported. “These findings suggest that perhaps a change in the infusion length could have an impact
Ceftobiprole. Ceftobiprole is an extended spectrum cephalosporin that
has activity against MRSA and penicillin-resistant S pneumoniae and
Research indicates that for concentration-independent anti-
limited activity against P aeruginosa and Acinetobacter species. It has a
microbial drugs such as the carbapenems, bactericidal activity is
3- to 4-hour half-life, and is administered as a pro-drug. Ceftobiprole
obtained when the time above the minimal inhibitory concentra-
tion (MIC) for the dosing interval reaches at least 40%. “Thus, a
Ceftobiprole studies indicate that the agent is effective in inhib-
4-hour infusion instead of a 30-minute infusion of doripenem may
iting the growth of 92% of 372 Enterobacteriaceaeisolates. This
make a great deal of sense,” said Martin.
includes ESBL- and AmpC-producing strains (Jones. Clin Microbiol Infect. 2007;13[suppl 2]:17). “Ceftobiprole is the only cephalosporin
Colistin and Polymyxin B. Although colistin and polymyxin B have
that has effective MRSA activity, as well as other staph infections,”
been around for decades, their use in the treatment of infections
Martin said. “It has a similar potency to linezolid or vancomycin
caused by gram-negative organisms is new. Both of these agents
are bactericidal and exert their action by binding to the phosphate
In summing up his presentation, Martin noted that more data
groups in the lipids of the cytoplasmic membrane of the organism.
are needed to learn about these new compounds. He also stressed that
They are active against nearly all gram-negative bacteria, except
the number of new antimicrobials is limited. “With that in mind, good
Proteus species, Burkholderia cepacia, Providencia species, Serratia marc-
stewardship of antimicrobial use is key to drug preservation,” he said. CWdW]_d]?dlWi_l[<kd]Wb?d\[Yj_edi
“Fungal infections are an important problem in the ICU,” said
cant–and certainly interesting–finding was that the blood did not
Pamela A. Lipsett, MD, FCCM, from Johns Hopkins University
clear as well with high-dose fluconazole therapy. At present, there is
School of Medicine and Nursing in Baltimore, Maryland. “In fact,
no recommendation to use high-dose fluconazole on a routine basis
10% of bloodstream infections in the ICU are caused by Candida spe-
or to use a combination of amphotericin and fluconazole,” Lipsett
cies, and these infections–the third most common seen in critical care
–have crude mortality rates ranging from 40% to 80%.”
In the echinocandin class, half-life differences are seen among
Approximately 72% of all fungal pathogens in the ICU are
the three agents. Anidulafungin, the most recently released of these
C albicans. The second most common ICU fungal pathogen is C
drugs, has the longest half-life (26.5 h) and the largest volume of
glabrata. Others include C tropicalis, C parapsilosis, and C krusei. In
distribution. It also is the only echinocandin that is metabolized
patients who have undergone solid organ transplantation or who
chemically, with no hepatic involvement.
have neutropenia, Aspergillus species and other molds are emerg-
ing as pathogens of concern. About 50% of respiratory and rectal
cultures and a smaller percentage of urinary and wound cultures
reveal the presence of fungi, but this does not necessarily signify
JWXb[($H_ia<WYjehie\<kd]Wb?d\[Yj_ediI[[d_dj^[?9K
infection. Rather, it is colonization that usually indicates infection.
H_ia<WYjeh FWj^e][d
(Laverdiere et al. J Crit Care. 2007;22:245; Pfaller et al. Clin Microbiol
“It is important to identify the fungal species, because some
are either resistant or partially susceptible to azole agents,” Lipsett
9WdZ_ZW"Jh_Y^eifehed"7if[h]_bbki
stated. For example, amphotericin may not be effective against C glabrata. Fluconazole should not be used against C krusei, which is
resistant to the agent. It is also ineffective in Aspergillus infections.
Clinicians also must be aware that fungi can have dose-depen-
dent sensitivity to antifungals: the larger the dose, the greater the
likelihood of eradication. “Some C glabrata infections, for instance,
require a higher than normal dose of fluconazole,” said Lipsett.
“Instead of administering a standard dose of 400 mg, you can give
an 800-mg dose and it will be effective. This is called dose-dependent
=[[hji[jWb$9^[ij$(&&-1''/0')(+
In discussing antifungal use, Lipsett defined some terms.
Treatment refers to therapy for proven or probable infections.
Empiric treatment refers to therapy given for suspected infection.
In the triazole class, voriconazole was found to be as effective
Preemptive treatment refers to therapy given when the patient has
as a regimen of amphotericin followed by fluconazole in the treat-
fungal colonization and risk factors for infection. When a patient
ment of candidemia in patients without neutropenia (Kullberg et al.
has risk factors but no known colonization, antifungal therapy is
Lancet. 2005;366:1435). “This would not be true for Aspergillus infec-
referred to as either general or targeted prophylaxis.
tions, however,” remarked Lipsett. “Voriconazole is actually more
“The problem is there are no consensus definitions about what a
effective than fluconazole in treating Asperigillus infections.”
fungal infection is and is not in patients who do not have neutropenia,”
Identifying patients at risk for candidemia is important, as they
stated Lipsett. According to the published microbiologic definition,
can develop this infection within the first 2 days of entering the
fungal infection consists of the following: detection of fungal ele-
ICU. “Many fungal pathogens grow slowly, so if you don’t suspect a
ments by cytology or direct microscopy from sterile fluids, detection of
fungal infection and you do not begin therapy empirically, there's a
Candida casts in the urine without a catheter, or detection of Candida in
high risk of mortality,” Lipsett said.
the blood (de Paw et al. Clin Infect Dis. 2005;41[suppl 6]:S377).
New guidelines from the Infectious Diseases Society of America
Intensivists need to be knowledgeable in the major risk factors
are expected to be released soon. These guidelines will include the
for various ICU fungal infections (see Table 2). Several risk factors
new agents that have established their non-inferiority in clinical trials
also have been identified for disseminated fungal disease: antibi-
and that might be better in some situations of resistance or toxicity.
otic therapy for longer than 6 days, treatment with three or more
Lipsett concluded her discussion of ICU fungal infections by
antimicrobial agents, acute renal failure, central venous catheter,
emphasizing the need to consider the possibility of fungal infection
age older than 40 years, gastrointestinal surgery, diabetes mellitus,
in high-risk patients. “Initial therapy needs to be timely and correct.
cancer, parenteral nutrition, trauma (multiple), steroids, burns and
Because of low rates of resistance to azole drugs, I believe fluconazole
is the drug of choice. However, if you are in a situation where there
“There is much excitement in antifungal drug development
are high rates of either azole resistance or C glabrata or C krusei organ-
today,” she said. “We now have a wide variety of treatment options
isms, echinocandins should be considered as first-line therapy.”
for candidemia.” These include amphotericin B deoxycholate, fluconazole (intravenous and oral), amphotericin B lipid complex
Supported by an educational grant from Pfizer, Inc.
(ABLC), amphotericin B colloidal dispersion (ABCD), liposomal amphotericin B, the three echinocandins that became available in 2007 (caspofungin, micafungin, and anidulafungin), and the new
9edj_dk_d];ZkYWj_edI[b\#7ii[iic[dj
tertiary azole agents (voriconazole and posaconazole).
In making a selection among these antifungals, the availability
<?=>J?D=J>;D;L;H#;D:?D=87JJB;7=7?DIJ7DJ?C?9HE8?7BH;I?IJ7D9;
of the agent must be determined. “Then you need to have some idea about the likely pathogen and be familiar with your local pathogens
)$ 7ced]fWj_[djim_j^l[dj_bWjeh#WYgk_h[Zfd[kced_W"Wdj_c_YheX_Wbj^[hWfo\eh'+ZWoi
and the sensitivity these pathogens,” stated Lipsett. “You also need to
mWiWiieY_Wj[Zm_j^bem[hcehjWb_johWj[iYecfWh[Zm_j^.ZWoie\Wdj_c_YheX_Wbj^[hWfo$
know if the patient has been exposed to any azole agents, which may
suggest development of a more resistant pathogen profile.”
According to a meta-analysis of studies comparing the use of
*$ M^_Y^e\j^[\ebbem_d]W][dji^Wi[\\_YWYoW]W_dijc[j^_Y_bb_d#h[i_ijWdjIjWf^obeYeYYki
flucanazole versus amphotericin in candidemia, no differences in
clinical or microbiologic response rates were found, but a greater
amount of toxicity was associated with amphotericin (Kontoyiannis
et al. Mycoses. 2001;44:125). Other data show generally no differ-
ences in efficacy outcomes between high-dose (800 mg) fluconazole compared with placebo and with fluconazole plus amphotericin
9ecfb[j[j^[feij#j[ijWjmmm$iYYc$eh]%9ed]h[iiH[l_[m&.$
(Rex et al. Clin Infect Dis. 2003;36:1221). “Perhaps the only signifi-
CE credit at www.sccm.org/CongressReview08
JUNE 2008
Europäisches Patentamt European Patent Office Office européen des brevets EP 0 989 848 B1 EUROPEAN PATENT SPECIFICATION (51) Int Cl.7: A61K 9/28 of the grant of the patent: 29.09.2004 Bulletin 2004/40 PCT/IB1998/000883 (21) Application number: 98921690.8 (22) Date of filing: 08.06.1998 WO 1998/056360 (17.12.1998 Gazette 1998/50) (54) FILM-COATED TABLET FOR IMP