Sludge Watch ==> Emerging new human pathogens create critical public health concerns
Maureen Reilly
maureen.reilly at sympatico.ca
Wed Apr 9 13:46:57 EDT 2008
Sludgewatch Admin:
This is a document in which researchers discuss how increasingly difficult
it is to treat the Gram-Negative bacteria that are infecting North
Americans.
Increasing antibiotic resistance in these bacteria means that it is harder
to find drugs that will help infected people to fight such infections.
Sewage sludge is full of Gram Negative bacteria. We have no business
trucking these pathogens out to rural communities where they are dispersed
into the environment and expose people, livestock and wildlife.
............................................
www.medscape.com
George H. Talbot
Expert Rev Anti Infect Ther. 2008;6(1):39-49.
Posted 04/03/2008
Abstract and Introduction
Abstract
The emergence of new human pathogens and increasing antimicrobial resistance
in well-established pathogens are critical public health concerns.
Unfortunately, the pipeline of new antimicrobial candidates remains
remarkably lean for molecules active against increasingly problematic
Gram-negative bacterial pathogens, such as Acinetobacter baumannii and
Pseudomonas aeruginosa. Although a number of new anti-Gram-negative
antibacterial agents are likely to be introduced soon for clinical use, they
will not represent a quantum leap in our ability to effectively treat these
human pathogens of great concern. New classes of antimicrobials with novel
mechanisms of action and new approaches to increasing the effectiveness of
traditional antimicrobials are urgently needed. Renewed research and
development efforts must become a priority, lest we fall further behind in
our therapeutic initiatives.
Introduction
The emergence of new human pathogens and the phenomenon of increasing
antimicrobial resistance in well-established pathogens are critical public
health concerns that most obviously impact patients and their physicians
but, in fact, truly affect each of us. In the world of Gram-positive
organisms, the increasing incidence of infections caused by
community-associated methicillin-resistant Staphylococcus aureus (MRSA) and
the rising rate of macrolide resistance in Streptococcus pyogenes are but
two of many concerns.[1,2] As for Gram-negative pathogens, one can readily
point to both the emergence of Acinetobacter baumannii as a cause of
hospital-acquired pneumonia (HAP) and the increasing rates of infections
with other multidrug-resistant Gram-negative bacilli, such as Klebsiella
pneumoniae, as examples.[2]
A number of these alarming developments were highlighted in the March 2006
publication: Bad bugs need drugs: an update on the development pipeline from
the Antimicrobial Availability Task Force of the Infectious Diseases Society
of America.[2] The Infectious Diseases Society of America (IDSA) identified
a 'hit list' of important pathogens based on two criteria: a current public
health concern due to a high incidence of infection, substantial morbidity,
high attributable mortality, or unique virulence or resistance factors, or a
combination of two or more of these characteristics; and few or no new
antimicrobial candidates in the late-stage development pipeline (defined as
Phase II or III of clinical development). The IDSA singled out three
increasingly problematic Gram-negative pathogens: Acinetobacter spp.,
including A. baumannii; Pseudomonas aeruginosa; and extended-spectrum
β-lactamase (ESBL)-producing Enterobacteriaceae. Following the IDSA's
lead, this article reviews those molecules in the development pipeline with
activity against Gram-negative pathogens, especially A. baumannii and P.
aeruginosa. The focus is on 'classical' antibacterial molecules with
meaningful in vitro activity against these organisms, as well as on
molecules with novel mechanisms of action. This review will not address
purely 'topical' therapy of lower respiratory tract infection with inhaled
compounds, such as aztreonam.
Acinetobacter baumannii: Resistance Par Excellence
As noted by the IDSA, A. baumannii is "a prime example of a mismatch between
unmet medical needs and the current antimicrobial research and development
pipeline".[2] Acinetobacter spp. infections cause substantial morbidity and
mortality in afflicted patients and are increasing in frequency.[3-5] For
example, data collected from 1995 through 2004 by the National Nosocomial
Infection Surveillance System examined 8537 infections caused by
Acinetobacter spp., with a total of 3601 isolates.[5] Pneumonia was the most
common infection site, accounting for 46% of all infections, followed by
bloodstream infections (13%) and skin and soft tissue infections (10%). The
analysis classified organisms as not susceptible to a given class of
antimicrobials if all isolates were intermediate or resistant in
susceptibility. It is striking that between 1995 and 2004, substantial
increases occurred in the prevalence of resistance to the major
antimicrobial treatment options for Acinetobacter spp. - fluoroquinolones,
noncarbapenem β-lactams, aminoglycosides and carbapenems. The rate of
resistance to fluoroquinolones increased from 50 to 73%, and to
β-lactams from 39 to 66% (p < 0.01 for each comparison). The increase
in aminoglycoside resistance was somewhat less, but worrisome nonetheless
(19-31%; p = 0.12). Even for the carbapenems, which demonstrate the greatest
inherent activity against A. baumannii, the frequency of resistance
increased by 30%, from 9 to 39% (p < 0.01). These changes in the
epidemiology and resistance rates of Acinetobacter spp. have led clinicians
to adopt therapeutic options, such as colistimethate sodium ('colistin',
also known as polymixin E), the use of which had previously been abandoned
due to toxicity.[6,7]
Two late-development phase molecules that are active in vitro against
multidrug-resistant Acinetobacter spp. have the potential to provide
incremental therapeutic benefit. In Phase II development, by Paratek
Pharmaceuticals, Inc., is the aminomethylcycline PTK-0796 (MK-2764,
MK-2764/PTK-0796, BAY 73-6944, BAY 73-7388).[8-12,101] Tigecycline
(Tygacil®, Wyeth Pharmaceuticals), which has been approved by regulatory
authorities in the USA, Europe and other regions for the treatment of
complicated skin and skin structure infection (cSSSI) and complicated
intra-abdominal infection (cIAI), is in late-stage development for therapy
of A. baumannii infection.[13-20] These molecules, which are derivatives of
minocycline and similarly act via protein synthesis inhibition, exhibit
improved antimicrobial activity over that of the parent molecule as a result
of being poor substrates for tetracycline efflux pumps.
PTK-0796 is currently under study in both an intravenous and an oral
formulation.[101] The oral formulation could be a particularly attractive
addition to the antimicrobial armamentarium. The molecule exhibits in vitro
activity against both aerobic Gram-positive and important aerobic
Gram-negative pathogens and is active in animal models of infection,
including pneumonia in neutropenic and normal mice and sepsis.[8-12]
PTK-0796 is active in vitro against methicillin-susceptible S. aureus
(MSSA), MRSA, penicillin-resistant Streptococcus pneumoniae,
vancomycin-resistant Enterococcus faecium and Enterococcus faecalis. A MIC90
of 2 µg/ml against Escherichia coli (n = 23) has also been demonstrated.[8]
Against A. baumannii, PTK-0796 exhibited a MIC90 of 8 µg/ml (n = 21) and a
MIC50 of 2 µg/ml (range: 0.12-16 µg/ml).[12] These 21 organisms were
moderately resistant to doxycycline (MIC90: 32 µg/ml) and also resistant to
ciprofloxacin, ceftriaxone, and piperacillin-tazobactam. In the abscence of
specific information on the pharmacokinetic (PK) profile of the compound at
the selected therapeutic dose, it is not possible to anticipate PTK-0796's
eventual utility in treatment of Gram-negative bacillary infections,
including those caused by A. baumannii, especially when it is administered
orally.
Tigecycline, for which only an intravenous formulation is available, is
currently in Phase IIIb study for the treatment of A. baumannii
infection.[19] Susceptibility testing of carbapenem-intermediate or
-resistant A. baumannii (n = 93) and Canadian intensive care unit
surveillance data (n = 27) demonstrate favorable in vitro activity with a
MIC90 of 2 µg/ml for Acinetobacter spp..[13,14] However, other data suggest
that, at least in some regions, the compound is less active.[15-18] A
postapproval study of its potential utility in the therapy of
multidrug-resistant Gram-negative infections included a small sample of 19
patients with A. baumannii infection, for whom a clinical cure rate of 82.4%
(14 of 17 evaluable patients) was achieved.[19] The MIC range of the
isolates in this study was 0.25-16 µg/ml. A limitation of the study is that
not all of the 19 patients received tigecycline monotherapy, so the exact
contribution of tigecycline in the cure of these patients is not clear. In a
separate study, the efficacy of tigecycline therapy of A. baumannii
pulmonary infection was examined in 25 patients with ventilator-associated
pneumonia (VAP; 19), VAP with bacteremia (three) or bacteremia alone
(three).[20] Microbiologic eradication was achieved in 12 (80%) of the 15
patients from whom repeat cultures were obtained.
Since tigecycline achieves modest plasma concentrations, its potential
efficacy against organisms with a higher MIC (i.e., >2 µg/ml) is
uncertain.[21] Although it is reassuring that tissue concentrations are
higher than those in plasma,[21] that pulmonary penetration has been
demonstrated[22] and that the drug is efficacious in treatment of
community-acquired pneumonia (CAP),[23] the recent failure of a Phase III
study in the HAP/VAP indication is concerning.[24] The exact role of
tigecycline, if any, in therapy of A. baumannii pulmonary infection remains
to be defined.
Another potential approach to therapy of A. baumannii (and P. aeruginosa)
infections is the use of novel β-lactamase inhibitors. Basilea
Pharmaceutica Ltd recently presented in vitro and animal in vivo data on a
new β-lactamase inhibitor/β-lactam combination, BAL30376.[25-27]
This tripartite compound is comprised of a siderophore monobactam (which is
stable to class B β-lactamases), plus a bridged monobactam (which
inhibits class C β-lactamases), plus clavulanate (which inhibits class
A β-lactamases). BAL30376 exhibited very good activity against a panel
of nonfermenting Gram-negative bacilli, including A. baumannii, P.
aeruginosa and Stenotrophomonas maltophilia, as well as against
Enterobacteriaceae with known β-lactamases[25,26] In addition, Meiji
Seika Kaisha reported clinically relevant in vitro and animal in vivo
activity of its metallo-β-lactamase inhibitor ME1071 (CP3242) against
A. baumannii (and P. aeruginosa).[28-30] Neither of these compounds has
entered clinical study.
Aside from these few molecules with an uncertain future, the pipeline for
multidrug-resistant A. baumannii is not encouraging.
Pseudomonas aeruginosa: Another Problem Pathogen
As noted by the IDSA, "multiple novel approaches to antipseudomonal drug
therapy are desperately needed".[2] Unfortunately, the near-term pipeline is
also lean for P. aeruginosa. One compound entering the market is doripenem
(Doribax®, Johnson & Johnson, S-4661), an intravenously administered
carbapenem that has completed Phase III studies for complicated urinary
tract infection (cUTI), cIAI, and HAP/VAP. Approved for marketing in Japan
in 2006, doripenem also recently received regulatory approval in the USA for
treatment of cUTI and cIAI.[102]
Doripenem exhibits excellent in vitro activity against P. aeruginosa; for
266 strains the MIC90 was 4 µg/ml (range: 0.03-32 µg/ml), as compared with
16 µg/ml for imipenem (range: 0.5 to >32 µg/ml).[31] Doripenem is most
active against North American strains of P. aeruginosa and least active
against those from Latin America, with those from Europe falling in an
intermediate range.[32] The same study showed that doripenem was somewhat
more active than either imipenem or meropenem against 1199 North American
strains.[32] Although doripenem is very active against P. aeruginosa strains
isolated from hospital-acquired infections, it is less potent against
isolates from cystic fibrosis patients.[33,34] Resistance mechanisms include
carbapenemases; loss of membrane permeability via OprD, which leads to a
notable increase in MIC; and overexpression of efflux pumps.[35,36]
Doripenem is also considerably less active against Acinetobacter spp., with
an MIC90 greater than 8 µg/ml.[32] The compound exhibits potent activity
against Citrobacter spp., Enterobacter cloacae, E. coli, K. pneumoniae and
Serratia marcescens, with MIC values at least 16-fold lower than those for
imipenem against the same isolates.[31]
The clinical efficacy of doripenem against P. aeruginosa infection was
assessed in two studies of the cIAI indication, for which doripenem was
administered at a dose regimen of 500 mg given by intravenous infusion over
60 min every 8 h.[37] Each study achieved its primary efficacy end point. In
a pooled analysis, doripenem achieved noninferiority to meropenem 1 g
administered as a 3-5-min intravenous bolus every 8 h, with a success rate
of 84.6% (275 of 325 subjects) versus 84.1% (260 of 309 subjects),
respectively.[37] For P. aeruginosa infections, a favorable response rate of
85% (34 of 40 subjects) was seen for doripenem, versus 75% (24 of 32
subjects) for the comparator.[37] Doripenem appeared relatively well
tolerated. Recently published data from two HAP/VAP studies are useful in
assessing the compound's utility against serious pseudomonal
infection.[38,39] In a study of VAP, doripenem 500 mg administered as a 4-h
infusion every 8 h achieved noninferiority to imipenem 500 mg every 6 h or
1000 mg every 8 h administered for 30 or 60 min.[38] Clinical cure rates for
P. aeruginosa were 65% (13 of 20) versus 36% (five of 14), respectively. In
a companion HAP study, noninferiority to a regimen of
piperacillin-tazobactam was achieved.[39] More strains of P. aeruginosa were
resistant to the comparators than to doripenem.[39] The results of these
studies indicate that doripenem will be a useful antipseudomonal
therapeutic, with a moderate improvement in in vitro and in vivo activity.
Another carbapenem, tomopenem (Daiichi Sankyo, formerly RO4908463, CS-023,
and R-115685), has advanced as far as Phase II of development for cSSSI and
HAP (Dannemann B, Pers. Comm.). In Japan, the compound has entered Phase I
study.[40] The activity of this compound against recent isolates of
clinically important pathogens has been reported.[41-45] This molecule has
meaningful in vitro activity against P. aeruginosa; the MIC90 for 100
strains was 4 µg/ml, and the MIC50 was 0.5 µg/ml (range: 0.06 to >32
µg/ml).[45] The compound was less active against 21 strains of
imipenem-resistant P. aeruginosa, with a MIC90 of 16 µg/ml (range: 1 to >32
µg/ml).[45] In healthy human volunteers, the compound exhibits linear
pharmacokinetics following intravenous administration with an elimination
half-life of approximately 1.5-2 h, which is notably longer than that of
other carbapenems.[40,46,47] Unfortunately, the development of this
carbapenem for countries outside of Japan appears to have been interrupted,
if not terminated, as it was recently announced that Roche had returned the
development rights to the innovator company.[48]
Ceftobiprole medocaril (Johnson & Johnson-Basilea Pharmaceutica; BAL5788),
the intravenous prodrug of the cephalosporin ceftobiprole (formerly
BAL9141), has completed Phase III studies in cSSSI, CAP and HAP.[49] A
marketing application for therapy of cSSSI was recently filed in the USA,
Canada and Europe.[103,104] Ceftobiprole is active in vitro against MRSA and
other Gram-positive pathogens, as well as against ceftazidime-susceptible
Gram-negative pathogens (e.g., Citrobacter spp., E. cloacae, E. coli, K.
pneumoniae, Proteus mirabilis, and S. marcescens), but it is not active
against ESBL producers.[50-57] Ceftobiprole also exhibits in vitro activity
against P. aeruginosa, generally comparable with that of ceftazidime, with a
MIC90 of 16 µg/ml.[54,57] The compound is not active against most
Acinetobacter spp..[52]
Published clinical data, which thus far are limited to the cSSSI indication,
suggest ceftobiprole will have considerable clinical utility. In its first
Phase III cSSSI study, the compound achieved noninferiority in clinical
response to a comparator of vancomycin, with a clinical cure rate of 93.3
versus 93.5%, respectively, in the clinically evaluable patient population,
and it demonstrated efficacy against MRSA cSSSI.[56] In a second Phase III
cSSSI study, noninferiority was shown against a comparator regimen of
vancomycin and ceftazidime; ceftobiprole was effective in treating cSSSI
caused by Gram-negative bacilli, as well as Gram-positive pathogens.[58] In
these studies, the MIC90 for strains of MRSA was 2 µg/ml.[53] Ceftobiprole
inhibited 75.6% (44 of 57) of Gram-negative isolates of 4 µg/ml or less; the
MIC90 for P. aeruginosa and A. baumannii was >64 µg/ml.[53] Results in CAP
and HAP patients have recently been announced, although not yet published as
of this article preparation.[105,106] In a single CAP study, noninferiority
to the comparator regimen of linezolid and ceftriaxone was achieved.[105]
Initially released results of the HAP study indicate that noninferiority to
comparator was achieved in the study population overall, but not in the VAP
subset.[106] Therefore, it is not yet possible to determine whether
ceftobiprole will be a clinically useful option for treatment of P.
aeruginosa pulmonary infection.
The cephalosporin FR264205 (Astellas Pharma, Inc., FK-037), a parenteral,
anti-Gram-negative compound in preclinical development, is active in vitro
against P. aeruginosa, including drug-resistant strains.[59] Against 193
strains of P. aeruginosa isolated in Japan, the MIC90 was 1 µg/ml (range:
0.25-4 µg/ml), as compared with an MIC90 of 16, 8 and 16 µg/ml for
ceftazidime, ciprofloxacin and imipenem, respectively.[59] This compound was
active in vitro against drug-resistant P. aeruginosa strains, including 13
that were ceftazidime resistant (the MIC90 of ceftazidime was 128 µg/ml), 35
that were imipenem resistant (the MIC90 of imipenem was 32 µg/ml), and 30
that were ciprofloxacin resistant (the MIC90 of ciprofloxacin was 64 µg/ml),
with a MIC90 of 4, 1 and 2 µg/ml, respectively. In vitro serial passage
studies have shown a low propensity for emerging resistance against
FR264205, which has also demonstrated activity in in vivo models.[59] It is
hoped that this promising compound, which was recently licensed by Calixa
Therapeutics, Inc., will soon advance to clinical study.
Novel Approaches to Acinetobacter spp. & Pseudomonas aeruginosa Infections
At a much earlier stage of development are approaches to therapy of
Acinetobacter spp. and P. aeruginosa infections that include efflux pump
inhibitors, antimicrobial peptides and their mimics, and antivirulence
drugs. The hypothesis supporting development of efflux pump inhibitors is
that they will exhibit synergism with antibiotic substrates of the membrane
transporters found in Gram-negative pathogens that extrude antimicrobials,
such as the fluoroquinolones, from the intracellular space.[60,61] Potential
routes of administration for efflux pump inhibitors include aerosol
inhalation and intravenous administration. Aerosol administration with
fluoroquinolones might be useful as topical therapy of cystic fibrosis and
HAP, whereas parenteral administration might be useful for therapy of
systemic infections.
Preclinical proof of concept has been shown in, for example, a neutropenic
murine model for the combination of levofloxacin and the efflux pump
inhibitor MC-02,595 (Mpex Pharmaceuticals, Inc.) against a strain of P.
aeruginosa overexpressing efflux pumps.[62] These data support in vitro work
demonstrating that the compound restores fluoroquinolone activity against P.
aeruginosa strains expressing a variety of efflux pumps, which increased
baseline fluoroquinolone MICs by as much as 512-fold.[63] Unfortunately, to
the author's knowledge, no efflux pump inhibitor is currently in clinical
development, probably reflecting the substantial challenges in the
efflux-inhibition approach. For example, efflux pumps are only part of the
problem of resistance in P. aeruginosa and Acinetobacter spp., as described
previously; in particular, fluoroquinolone resistance in P. aeruginosa is
also caused by point mutations in the target proteins, DNA gyrases and
topoisomerases. Other potential issues include the redundancy of efflux
pumps; inability for the efflux pump inhibitor to achieve activity at the
infection site, especially in systemic infection; and difficulties of
ensuring PK compatibility with the partner antimicrobial. The final
consideration is the potential for toxicity, given that efflux pumps in
bacteria are similar to those found in cells in important human organs, such
as the kidney and liver.
Another potentially useful approach to therapy of resistant Gram-negative
pathogens is represented by the antimicrobial peptides, which are cationic
peptides found widely in nature, including in humans.[64] These peptides,
which are part of the innate immune system, can be constitutively or
inducibly expressed. They demonstrate antiviral, antibacterial and/or
antifungal activity by being either direct microbicides or effector
molecules in the immune system. The antibacterial activity of these peptides
is achieved by disruption of membrane structures and an increase in cell
membrane permeabilization; interference with cell wall, DNA and protein
synthesis; or activity on important intracellular enzymes; or by a
combination of two or more of these mechanisms.[64]
Some antimicrobial peptides have demonstrated activity against important
human pathogens in preclinical studies. For example, cecropin A-melittin
hybrid peptides exhibited bactericidal activity against A. baumannii, with a
MIC range of 2-8 ug/ml.[65] Chaperone Technologies, Inc. has demonstrated
that its compound CHP105 inhibits DnaK, a protein-folding enzyme, thereby
achieving in vitro synergy with fluoroquinolones against strains of certain
Enterobacteriaceae: E. coli, K. pneumoniae, E. cloacae and Citrobacter
freundii.[66] Ceragenix Pharmaceuticals, Inc., is also examining
antimicrobial peptides, such as CSA-13, which is a membrane-active peptide
mimic with broad antibacterial activity, including activity against P.
aeruginosa.[67-70] This molecule has demonstrated activity in biofilm and in
an environment characteristic of the airway fluid of cystic fibrosis
patients.[69,70] An interesting topical compound is omiganan
pentahydrochloride (Omigard™; Cadence Pharmaceuticals, Inc.), a topical
cationic peptide in an aqueous gel currently in development for the
prevention of intravascular catheter-related local infections.[71,107]
As with the efflux pump inhibitors, there are many challenges to successful
development of antimicrobial peptides for human therapeutics. Several
antimicrobial peptides have previously failed in human development,
including pexiganan (Genaera Corporation, Inc.) for diabetic foot infection,
iseganan (Intrabiotics Pharmaceuticals, Inc.) for oral mucositis associated
with chemotherapy, and P113D (Pacgen Biopharmaceuticals Corporation) as
treatment for P. aeruginosa infections in patients with cystic fibrosis.[64]
Pragmatic considerations include potential toxicity due to lack of
selectivity of peptide antibiotics for the bacterial, as opposed to the
mammalian, cell membrane, and the fact that the most feasible administration
route is topical, because peptides are susceptible to proteolytic
degradation in vivo.[64]
Antivirulence drugs are also at an early preclinical stage of development.
For example, Mutabilis Pharmaceuticals is developing inhibitors of RfaE and
WaaC, enzymes involved in the synthesis of inner core lipopolysaccharides in
Gram-negative bacilli.[72,73] RfaE catalyzes phosphorylation of constituents
of the inner core lipopolysaccharide of Gram-negative bacilli. Deletion of
these enzymes results in greater susceptibility of Gram-negative bacilli to
human serum in vitro and attenuated virulence in vivo.[72,73] Although
scientifically this approach is very interesting, there are substantial
pragmatic development challenges; for example, with current technology, it
will be difficult to measure the efficacy of such inhibitors in standard in
vitro testing systems.
Other Antimicrobials in the Pipeline With Activity Against Gram-negative
Pathogens
A number of molecules exhibit useful activity against clinically important
Gram-negative pathogens other than P. aeruginosa and A. baumannii. The
parenteral, broad-spectrum, cephalosporin prodrug ceftaroline fosamil
(Cerexa, Inc. and Forest Laboratories; PPI-0903, TAK-599, ceftaroline
acetate), has recently entered Phase III studies [74, data on file, Cerexa,
Inc.]. Ceftaroline has been granted fast-track designation by the US FDA for
treatment of cSSSI. This bactericidal compound is converted rapidly in vivo
to the bioactive metabolite ceftaroline, which is very active in vitro
against MRSA and other drug-resistant Gram-positive pathogens, such as
coagulase-negative staphylococci.[75-78] Ceftaroline's Gram-negative
spectrum, which is comparable to that of ceftriaxone, comprises Haemophilus
influenzae, Moraxella catarrhalis and other ceftazidime-susceptible,
Gram-negative pathogens, but not ESBL-producing Enterobacteriaceae, P.
aeruginosa, or Acinetobacter spp..[75,76] In a recently completed Phase II
study, ceftaroline was compared with vancomycin with or without aztreonam
for therapy of cSSSI.[74] In the clinically evaluable population,
ceftaroline achieved a clinical cure rate of 96.7% (compared with 88.9% for
the comparator regimen), with a very favorable safety and tolerability
profile.[74] In this clinical study, the MIC90 for MRSA was 0.5 µg/ml and
that for MSSA, 0.25 µg/ml; ceftaroline inhibited 100% (87 of 87) of
Gram-positive isolates and 92.0% (23 of 25) of Gram-negative isolates at 4
µg/ml.[78] This compound holds promise as a therapy for serious
community-acquired infections caused by both Gram-negative and Gram-positive
pathogens.
Protez Pharmaceuticals, Inc. is developing a novel parenteral carbapenem,
PZ-601 (SMP-601, SM-216601). This compound is active in vitro against
Gram-positive pathogens including MRSA (MIC90 range: 2-4 µg/ml)[79-81] and
various Gram-negative pathogens,[82] excluding P. aeruginosa (MIC90: 64
µg/ml) and A. baumannii (MIC90: 64 µg/ml). The compound retains activity
against ESBL-producing E. coli (MIC90: 2 vs 0.25 ug/ml for imipenem);
however, against ESBL-producing K. pneumoniae (n = 29), its potency was
lower (MIC90: 8 vs 4 µg/ml for imipenem).[82] PZ-601 was well tolerated in
single- and multiple-dose Phase I studies; PK data from these studies have
informed the dose selection strategy.[83,84] PZ-601 will soon be entering
Phase II study (Young C, Pers. Comm.).
ME1036 (CP5609), a DHP-1-stable carbacephem licensed by Cerexa, Inc. and
Forest Laboratories from Meiji Seika Kaisha Ltd., which demonstrates
excellent in vitro activity against multidrug-resistant staphylococci and E.
faecalis (including vancomycin-resistant strains), exhibits the broad
Gram-negative activity of the carbapenems (e.g., activity against
ESBL-producing E. coli and K. pneumoniae), except P. aeruginosa.[85-87] This
compound recently entered Phase I study in an intravenous formulation [data
on file, Cerexa, Inc].
Both PZ-601 and ME1036 could be useful therapeutic options for serious
community- and hospital-acquired infections caused by both Gram-negative and
Gram-positive pathogens.
In addition to the Basilea β-lactamase inhibitor BAL30376 discussed
previously, Novexel and Wyeth each has a novel β-lactamase inhibitor in
development. NXL104 (Novexel; previously AVE1330A and recently licensed by
Cerexa Inc. and Forest Laboratories) is active against class A and class C
β-lactamases.[88,89] The addition of NXL104 to the β-lactams
cefpodoxime, cefixime and ceftazidime restores the in vitro activity of
these agents against class A and class C β-lactamase-producing
Enterobacteriaceae.[89,90] In vivo antibacterial activity has been shown in
murine sepsis and pneumonia.[91] Additional preclinical data show that the
drug has a low potential for drug-drug interactions, no systemic toxicity in
animal studies, no genotoxicity, and a solubility and stability profile
compatible with intravenous administration.[88] In a single-dose Phase I
study, NXL104 was safe and well tolerated to a dose of 2000 mg, with linear
PK and a plasma half-life of 1.5-2.7 h.[92]
Wyeth Pharmaceuticals recently presented data on its new β-lactamase
inhibitor, BLI-489; this molecule is a penem that exhibits excellent
activity against class A, C and D β-lactamases.[93,94] The combination
of BLI-489 with piperacillin enhances the activity of the latter against P.
aeruginosa, as well as against β-lactamase-producing
Enterobacteriaceae. Lek Pharmaceuticals is also investigating
β-lactamase inhibitors, including a tricyclic carbapenem LK-157.[95,96]
These compounds could be of great value if successfully advanced to the
clinic.
Conclusion
While the compounds discussed in this review represent a glimmer of hope for
the short and intermediate terms, it is clear that the development pipeline
remains remarkably lean for molecules highly active against the most
problematic Gram-negative pathogens, including A. baumannii and P.
aeruginosa. The antibacterial agents likely to be available for use in the
near future will not represent a quantum leap in our ability to effectively
treat these human pathogens of great concern. There will, however, be
additional choices of compounds with activity against common Gram-negative
pathogens, including some with enhanced Gram-positive activity. Most of
these new compounds, as analogs of existing molecules, represent next
'generations' of older classes. Accordingly, their targets are not novel.
Furthermore, most of these molecules are not fresh from the active discovery
research laboratories of major pharmaceutical companies in the USA or
Europe. Indeed, the majority of the innovator companies are based in Japan.
While we can be thankful for the foresight and success of our Japanese
colleagues in addressing current medical needs in antibacterial drug
therapy, we must be concerned, as the IDSA has highlighted, that the lack of
a worldwide, robust discovery infrastructure will haunt us increasingly in
the near future. New classes of antimicrobials with novel mechanisms of
action and new approaches to increasing the effectiveness of current
antimicrobials are urgently needed. Accordingly, renewed research and
development efforts must become a priority, lest we fall further behind in
our therapeutic initiatives.
Expert Commentary and Five-year View
The apparent substantial breadth and depth of the antimicrobial development
pipeline for problematic Gram-negative pathogens is misleading. Although
some important molecules are in later-stage clinical development for A.
baumannii and P. aeruginosa, none represent more than an incremental
advance. A look at earlier-stage compounds is a bit more encouraging;
however, given the vagaries of drug development, there is no assurance that
the paucity of therapeutic options for these 'bad bugs', will have been
addressed substantially by 2012. This part of the antibacterial landscape
contrasts with that for the Enterobacteriaceae and multidrug-resistant
Gram-positive pathogens. In this latter area, one can anticipate the
availability of ceftobiprole medocaril, ceftaroline fosamil, ME1036, PZ-601
and a variety of new β-lactamase inhibitor/β-lactam combinations.
Portions of this manuscript were presented at the 46th Interscience
Conference on Antimicrobial Agents and Chemotherapy, San Francisco, CA, USA
27-30 September (2006) and the Annual Meeting of the Infectious Diseases
Society of America, San Diego, CA, USA October (2007).
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and AmpC producing strains of Enterobacteriaceae. Proceedings of the 46th
Interscience Conference on Antimicrobial Agents and Chemotherapy. San
Francisco, CA, USA, 27-30 September (2006) (Abstract F-127).
* The in vitro profile of Novexel's β-lactamase inhibitor suggests it
would be a useful addition to the anti-infective armamentarium.
Robbins MJ, Cassettari M, Dencer C et al. In vitro activity of NXL104 (NXL),
a new β-lactamase inhibitor, in combination with cefpodoxime (CPD) and
cefixime (CFM) against 3rd generation cephalosporin-resistant isolates of
species of the Enterobacteriaceae. Proceedings of the 45th Interscience
Conference onAntimicrobial Agents and Chemotherapy. Washington, DC, USA,
16-19 December (2005) (Abstract F-1161).
Levasseur P, Girard AM, Miossec C, Lowther J, Rangaraju M, Hodgson J.
Efficacy of NXL104 (previously AVE1330A), a novel broad spectrum
β-lactamase inhibitor, in combination with ceftazidime (CAZ) in murine
septicaemia and pneumonia. Proceedings of the 45th Interscience Conference
on Antimicrobial Agents and Chemotherapy. Washington, DC, USA, 16-19
December (2005) (Abstract F-1164).
Merdjan H, Tarral A, Girard AM et al. Safety, single dose pharmacokinetics,
and pharmacodynamics of β-lactamase inhibitor NXL104 in healthy young
male adults. Proceedings of the 47th Interscience Conference on
Antimicrobial Agents and Chemotherapy. Chicago, IL, USA, 17-20 September
(2007) (Abstract A-809).
Petersen PJ, Jones CH, Bradford PA. In vitro activity of piperacillin in
combination with the penem β-lactamase inhibitor BLI-489 against a
predictor panel of characterized -lactamase producing organisms. Proceedings
of the 47th Interscience Conference on Antimicrobial Agents and
Chemotherapy. Chicago, IL, USA, 17-20 September (2007) (Abstract F1-322).
Petersen PJ, Jones CH, Bradford PA. In vivo efficacy of the penem
β-lactamase inhibitor BLI-489 in combination with piperacillin in
murine infection models. Proceedings of the47th Interscience Conference on
Antimicrobial Agents and Chemotherapy. Chicago, IL, USA, 17-20 September
(2007) (Abstract F1-323).
Prezelj A, Plantan I, Vilfan G et al. 10-ethylidene trinems as broad
spectrum β-lactamase inhibitors. Proceedings of the 47th Interscience
Conference on Antimicrobial Agents and Chemotherapy. Chicago, IL, USA, 17-20
September (2007) (Abstract F1-316).
Kresken M, Brauers J, Prezelj A. In vitro activity of LK-157, a novel
tricyclic carbapenem β-lactamase inhibitor. Proceedings of the 47th
Interscience Conference on Antimicrobial Agents and Chemotherapy. Chicago,
IL, USA, 17-20 September (2007) (Abstract F1-338).
Websites
Paratek press release: Paratek Pharmaceuticals announces the close of $40
million private placement to finance programs to combat MRSA infections
www.paratekpharm.com
US FDA press release: FDA approves new drug to treat complicated urinary
tract and intra-abdominal infections
www.fda.gov/bbs/topics/NEWS/2007/NEW01728.html
Basilea press release: Basilea announces filing of new drug submission in
Canada for ceftobiprole www.basilea.com
Basilea press release: US FDA and European EMEA accept registration
applications for ceftobiprole, a novel anti-MRSA broad-spectrum
cephalosporin www.basilea.com
Basilea press release: Basilea announces positive top-line data from Phase
III study of ceftobiprole in community-acquired pneumonia requiring
hospitalization www.basilea.com
Basilea press release: Basilea announces positive top-line data from phase
III study of ceftobiprole in hospital-acquired pneumonia. www.basilea.com
Cadence Pharmaceuticals product pipeline
www.cadencepharm.com/products/omigard.html
Sidebar: Key Issues
The emergence of Acinetobacter baumannii as a cause of hospital-acquired
pneumonia and the increasing rates of infections with other
multidrug-resistant Gram-negative bacilli, such as Klebsiella pneumoniae,
exemplify disturbing epidemiological trends that pose severe problems for
patients and their physicians.
Late-stage development molecules active in vitro against some
multidrug-resistant Acinetobacter spp. are the aminomethylcycline PTK-0796
and the glycylcycline tigecycline.
Doripenem represents a useful advance for therapy of Pseudomonas aeruginosa
infection. Tomopenem, ceftobiprole medocaril and FR264205 demonstrate
potentially useful activity against this pathogen.
Other 'classical' antimicrobials with interesting Gram-negative activity
include ceftaroline fosamil and the carbapenems ME1036 and PZ-601.
Novel β-lactamase inhibitors, such as NXL104, BLI-489 and BAL30376, and
β-lactam/β-lactamase inhibitor combinations also offer promise.
Nontraditional approaches, such as efflux pump inhibitors and antivirulence
drugs, are far from the clinic.
New classes of antimicrobials with novel mechanisms of action and new
approaches to increasing the effectiveness of current antimicrobials are
urgently needed.
Acknowledgements
The following individuals provided invaluable assistance: George Eliopoulos
(Harvard Medical School, USA); David Livermore (Health Protection Agency,
UK); Patricia Bradford, Evelyn Ellis-Grosse, and Timothy Babinchak (Wyeth
Pharmaceuticals); Ann Macone and Robert Arbeit (Paratek Pharmaceuticals,
Inc.); Karen Bush and Robert Flamm (Johnson & Johnson); Brian Dannemann
(Hoffmann La Roche, Inc.); Michael Dudley, Olga Lomovskay and Matthew Wikler
(Mpex Pharmaceuticals, Inc.); Clarence Young and John Pace (Protez
Pharmaceuticals, Inc.); Christine Miossec-Bartoli (Novexel). The author very
much appreciates James Ge's critical review of the manuscript, Ms Dee Dee
Hilgesen's administrative assistance, and Sandra Ruhl's medical writing
support. Sandra Ruhl is employed by Cerexa, Inc.
Reprint Address
George H. Talbot, Talbot Advisors, LLC. PO Box 7440, St Davids, PA 19087.
Tel.: +1 610 964 0946; Fax: +1 610 964 9338. talbot at aya.yale.edu
George H. Talbot, Executive Vice President and Chief Medical Officer,
Cerexa, Inc., 1751 Harbor Bay Parkway, Alameda, CA 94502
Disclosure: The author was an employee of Cerexa, Inc., when this manuscript
was prepared and now provides consultative services to Cerexa Inc. and
Calixa Therapeutics, Inc., as well as to other biopharmaceutical companies.
The author has no other relevant affiliations or financial involvement with
any organization or entity with a financial interest in or financial
conflict with the subject matter or materials discussed in the manuscript
apart from those disclosed.
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