During recent decades, we have seen an increasing number of reports
on the progressive development of bacterial resistance to almost all
available antimicrobial agents. In the 1970s, the major problem was
the multidrug resistance of Gram-negative bacteria, but later in the
1980s the Gram-positive bacteria became important, including methicillin-
resistant staphylococci, penicillin-resistant pneumococci and
vancomycin-resistant enterococci.25 In the past, the solution to the
problem has depended primarily on the development of novel
Microbial drug discovery antimicrobial agents. However, the number of new classes of antimicrobial
agents being developed has decreased dramatically in recent
years.
The advent of resistant Gram-positive bacteria has been noticed by
the pharmaceutical, biotechnology and academic communities. Some
of these groups are making concerted efforts to find novel antimicrobial
agents to meet this need. A new glycopeptide antibiotic, teicoplanin,
was developed against infections with resistant Gram-positive
bacteria, especially bacteria resistant to the glycopeptide vancomycin.
In another instance, the approach involved the redesign of a mixture
of two compounds, called streptogramin, into a new mixture, called
pristinamycin, to allow administration of the drug parenterally and in
higher doses than the earlier oral preparation.26 The two components
of streptogramin, quinupristin and dalfopristin, were chemically
modified to allow intravenous administration. The new combination,
pristinamycin, was approved by the FDA for use against infections
caused by vancomycin-resistant Enterococcus faecium.
Additional moves against resistant microorganisms are the glycylcyclines
developed to treat tetracycline-resistant bacteria. These modified
tetracyclines show potent activity against a broad spectrum of
Gram-positive and Gram-negative bacteria, including strains that
carry the two major tetracycline-resistance determinants, involving
efflux and ribosomal protection. Two of the glycylcyline derivatives,
DMG-MINO and DMG-DMDOT, have been tested against a large
number of clinical pathogens isolated from various sources. The
spectrum of activity of these compounds includes organisms with
resistance to antibiotics other than tetracyclines; for example, methicillin-
resistant staphylococci, penicillin-resistant S. pneumoniae and
vancomycin-resistant enterococci.27 Tigecycline was approved by the
FDA in 2005 as an injectable antibiotic.28
Among the novel class of antimicrobial agents used in treating
resistance to Gram-positive infections, we can also mention the cyclic
lipopeptide antibiotic daptomycin produced by Streptomyces roseosporus.
This compound was approved in 2003 by the FDA for skin
infections resulting from complications following surgery, diabetic
foot ulcers and burns. It represents the first new natural antibiotic
approved in many years. Its mode of action is distinct from any other
approved antibiotic: it rapidly kills Gram-positive bacteria by disrupting
multiple aspects of bacterial membrane function (by binding
irreversibly to the bacterial cell membrane, causing membrane depolarization,
destroying the ion concentration gradient and provoking
the efflux of K+). It acts against most clinically relevant Gram-positive
bacteria (Staphylococcus aureus, Streptococcus pyogenes, Streptococcus
agalactiae, Streptococcus dysgalactiae subsp. equisimilis and Enterococcus
faecalis), and retains in vitro potency against isolates resistant to
methicillin, vancomycin and linezolid. Traditionally, these infections
were treated with penicillin and cephalosporins, but resistance to these
agents became widespread.29–32 Daptomycin seems to have a favorable
side effect profile, and it might be used to treat patients who cannot
tolerate other antibiotics.
Telithromycin, a macrolide antibiotic, is the first orally active
compound of a new family of antibacterials named the ketolides. It
shows potent activity against pathogens implicated in communityacquired
respiratory tract infections, irrespective of their b-lactam,
macrolide or fluoroquinolone susceptibility. Some of the microorganisms
susceptible to this antibiotic are pneumococci, H. influenzae and
Moraxella catarrhalis, including b-lactamase-positive strains. In addition,
telithromycin has a very low potential for selection of resistant
isolates or induction of cross-resistance found with other macrolides.33
Clavulanic acid, first detected in Streptomyces clavuligerus, contains
a bicyclic b-lactam ring fused to an oxazolidine ring with an oxygen in
place of a sulfur, a b-hydroxyethylidene substituent at C-2 and no
acylamino group at C-6. It was first described in 1976 and shown to be
a potent inhibitor of the b-lactamases produced by staphylococci and
plasmid-mediated b-lactamases of E. coli, Klebsiella, Proteus, Shigella,
Pseudomonas and Haemophilus. Although it is a broad-spectrum
antibiotic, clavulanic acid possesses only very low antibacterial activity.
Therefore, the molecule has been combined, as a b-lactamase inhibitor,
with a variety of broad-spectrum semisynthetic penicillins. For
example, when administered with amoxicillin, it is used for the
treatment of infections caused by b-lactamase-producing pathogenic
bacteria.34 It has world sales of over US$1 billion, and in 1995 it was
the second largest selling antibacterial drug. Clavulanic acid can also
be combined with ticarcillin, which is a penicillin effective against
organisms such as E. coli, Proteus, Salmonella, Haemophilus, Pseudomonas
and S. aureus. It is normally used in hospitals for treating severe
infections affecting blood or internal organs, bones and joints, upper
or lower airways or skin and soft tissue. The combination extends
ticarcillin antimicrobial activity by inhibiting the action of the
b-lactamases produced by certain bacteria.
MOVES AGAINST RESISTANCE TO ANTIFUNGAL AGENTS
Mycosis is a condition in which fungi pass the resistance barriers of the
human or animal body and establish infections. These organisms are
harmless most of the time, but sometimes they can cause fungal
infections. In most cases, these infections are not life threatening.
However, when they are deeply invasive and disseminated, they lead to
more serious infections, particularly in critically ill patients, elderly
people and those who have conditions that affect the immune system
(by disease or through the use of immunosuppressive agents).
In addition, the use of antineoplastic and broad-spectrum antibiotics,
prosthetic devices and grafts, and more aggressive surgery has
increased invasive fungal infections. Patients with burns, neutropenia,
pancreatitis or after organ transplantation (40% of liver transplants,
15–35% of heart transplants and 5% of kidney transplants) are also
predisposed to fungal infection.35 Approximately 40% of death from
nosocomial infections are caused by fungi, and 80% of these are
caused by Candida and Aspergillus, although Cryptococcus spp.,
Fusarium spp., Scedosporium spp., Penicillium spp. and zygomycetes
are increasingly involved.36 Pulmonary aspergillosis is the main factor
involved in the death of recipients of bone marrow transplants, and
Pneumocystis carinii is the leading cause of death in AIDS patients
from Europe and North America.
The rising incidence of invasive fungal infections and the emergence
of broader fungal resistance have led to the need for novel antifungal
agents. Amphotericin B is the first-line therapy for systemic infection
because of its broad spectrum and fungicidal activity. However,
considerable side effects limit its clinical utility. Echinocandins are
large lipopeptide molecules that inhibit the synthesis of 1,3-b-Dglucan,
a key component of the fungal cell wall. Three echinocandins
(caspofungin, micafungin and anidulafungin) have reached the market.
Caspofungin is also known as pneumocandin or MK-0991.
This compound was the first cell-wall-active antifungal approved as
a new injectable antifungal; this was in 2000.38 It irreversibly inhibits
1,3-b-D-glucan synthase, preventing the formation of glucan polymers
and disrupting the integrity of fungal cell walls.39 It is more active and
less toxic than amphotericin B and shows a broad spectrum of activity
against Candida (including fluconozole resistance), Aspergillus,
Histoplasma and P. carinii, the major cause of HIV death. Micafungin
is licensed for clinical use in Asian countries and in the US. This
compound exhibits extremely potent antifungal activity against
clinically important fungi, including Aspergillus and azole-resistant
Microbial drug discovery strains of Candida.
In animal studies, micafungin is as efficacious
as amphotericin B with respect to improvement of survival rate.
It is characterized by a linear pharmacokinetic profile and
substantially fewer toxic effects. Anidulafungin is currently licensed
in the US.40
Although several new antifungal drugs have been developed in the
past 6 years, some patients remain resistant to treatments. The main
reasons for this include intrinsic or acquired antifungal resistance,
organ dysfunction preventing the use of some agents and drug
interactions. In addition, some drugs penetrate poorly into sanctuary
sites, including the eye and urine, and others are associated with
considerable adverse events. However, there has been some progress.
Posaconazole is a new member of the triazole class of antifungals.
It has shown clinical efficacy in the treatment of oropharyngeal candidiasis
and has potential as a salvage therapy for invasive aspergillosis,
zygomycosis, cryptococcal meningitis and a variety of other fungal
infections. It is available as an oral suspension and has a favorable
toxicity profile. The wide spectrum of posaconazole activity in in vitro
studies, animal models and preliminary clinical studies suggests that it
represents an important addition to the antifungal armamentarium.
on the progressive development of bacterial resistance to almost all
available antimicrobial agents. In the 1970s, the major problem was
the multidrug resistance of Gram-negative bacteria, but later in the
1980s the Gram-positive bacteria became important, including methicillin-
resistant staphylococci, penicillin-resistant pneumococci and
vancomycin-resistant enterococci.25 In the past, the solution to the
problem has depended primarily on the development of novel
Microbial drug discovery antimicrobial agents. However, the number of new classes of antimicrobial
agents being developed has decreased dramatically in recent
years.
The advent of resistant Gram-positive bacteria has been noticed by
the pharmaceutical, biotechnology and academic communities. Some
of these groups are making concerted efforts to find novel antimicrobial
agents to meet this need. A new glycopeptide antibiotic, teicoplanin,
was developed against infections with resistant Gram-positive
bacteria, especially bacteria resistant to the glycopeptide vancomycin.
In another instance, the approach involved the redesign of a mixture
of two compounds, called streptogramin, into a new mixture, called
pristinamycin, to allow administration of the drug parenterally and in
higher doses than the earlier oral preparation.26 The two components
of streptogramin, quinupristin and dalfopristin, were chemically
modified to allow intravenous administration. The new combination,
pristinamycin, was approved by the FDA for use against infections
caused by vancomycin-resistant Enterococcus faecium.
Additional moves against resistant microorganisms are the glycylcyclines
developed to treat tetracycline-resistant bacteria. These modified
tetracyclines show potent activity against a broad spectrum of
Gram-positive and Gram-negative bacteria, including strains that
carry the two major tetracycline-resistance determinants, involving
efflux and ribosomal protection. Two of the glycylcyline derivatives,
DMG-MINO and DMG-DMDOT, have been tested against a large
number of clinical pathogens isolated from various sources. The
spectrum of activity of these compounds includes organisms with
resistance to antibiotics other than tetracyclines; for example, methicillin-
resistant staphylococci, penicillin-resistant S. pneumoniae and
vancomycin-resistant enterococci.27 Tigecycline was approved by the
FDA in 2005 as an injectable antibiotic.28
Among the novel class of antimicrobial agents used in treating
resistance to Gram-positive infections, we can also mention the cyclic
lipopeptide antibiotic daptomycin produced by Streptomyces roseosporus.
This compound was approved in 2003 by the FDA for skin
infections resulting from complications following surgery, diabetic
foot ulcers and burns. It represents the first new natural antibiotic
approved in many years. Its mode of action is distinct from any other
approved antibiotic: it rapidly kills Gram-positive bacteria by disrupting
multiple aspects of bacterial membrane function (by binding
irreversibly to the bacterial cell membrane, causing membrane depolarization,
destroying the ion concentration gradient and provoking
the efflux of K+). It acts against most clinically relevant Gram-positive
bacteria (Staphylococcus aureus, Streptococcus pyogenes, Streptococcus
agalactiae, Streptococcus dysgalactiae subsp. equisimilis and Enterococcus
faecalis), and retains in vitro potency against isolates resistant to
methicillin, vancomycin and linezolid. Traditionally, these infections
were treated with penicillin and cephalosporins, but resistance to these
agents became widespread.29–32 Daptomycin seems to have a favorable
side effect profile, and it might be used to treat patients who cannot
tolerate other antibiotics.
Telithromycin, a macrolide antibiotic, is the first orally active
compound of a new family of antibacterials named the ketolides. It
shows potent activity against pathogens implicated in communityacquired
respiratory tract infections, irrespective of their b-lactam,
macrolide or fluoroquinolone susceptibility. Some of the microorganisms
susceptible to this antibiotic are pneumococci, H. influenzae and
Moraxella catarrhalis, including b-lactamase-positive strains. In addition,
telithromycin has a very low potential for selection of resistant
isolates or induction of cross-resistance found with other macrolides.33
Clavulanic acid, first detected in Streptomyces clavuligerus, contains
a bicyclic b-lactam ring fused to an oxazolidine ring with an oxygen in
place of a sulfur, a b-hydroxyethylidene substituent at C-2 and no
acylamino group at C-6. It was first described in 1976 and shown to be
a potent inhibitor of the b-lactamases produced by staphylococci and
plasmid-mediated b-lactamases of E. coli, Klebsiella, Proteus, Shigella,
Pseudomonas and Haemophilus. Although it is a broad-spectrum
antibiotic, clavulanic acid possesses only very low antibacterial activity.
Therefore, the molecule has been combined, as a b-lactamase inhibitor,
with a variety of broad-spectrum semisynthetic penicillins. For
example, when administered with amoxicillin, it is used for the
treatment of infections caused by b-lactamase-producing pathogenic
bacteria.34 It has world sales of over US$1 billion, and in 1995 it was
the second largest selling antibacterial drug. Clavulanic acid can also
be combined with ticarcillin, which is a penicillin effective against
organisms such as E. coli, Proteus, Salmonella, Haemophilus, Pseudomonas
and S. aureus. It is normally used in hospitals for treating severe
infections affecting blood or internal organs, bones and joints, upper
or lower airways or skin and soft tissue. The combination extends
ticarcillin antimicrobial activity by inhibiting the action of the
b-lactamases produced by certain bacteria.
MOVES AGAINST RESISTANCE TO ANTIFUNGAL AGENTS
Mycosis is a condition in which fungi pass the resistance barriers of the
human or animal body and establish infections. These organisms are
harmless most of the time, but sometimes they can cause fungal
infections. In most cases, these infections are not life threatening.
However, when they are deeply invasive and disseminated, they lead to
more serious infections, particularly in critically ill patients, elderly
people and those who have conditions that affect the immune system
(by disease or through the use of immunosuppressive agents).
In addition, the use of antineoplastic and broad-spectrum antibiotics,
prosthetic devices and grafts, and more aggressive surgery has
increased invasive fungal infections. Patients with burns, neutropenia,
pancreatitis or after organ transplantation (40% of liver transplants,
15–35% of heart transplants and 5% of kidney transplants) are also
predisposed to fungal infection.35 Approximately 40% of death from
nosocomial infections are caused by fungi, and 80% of these are
caused by Candida and Aspergillus, although Cryptococcus spp.,
Fusarium spp., Scedosporium spp., Penicillium spp. and zygomycetes
are increasingly involved.36 Pulmonary aspergillosis is the main factor
involved in the death of recipients of bone marrow transplants, and
Pneumocystis carinii is the leading cause of death in AIDS patients
from Europe and North America.
The rising incidence of invasive fungal infections and the emergence
of broader fungal resistance have led to the need for novel antifungal
agents. Amphotericin B is the first-line therapy for systemic infection
because of its broad spectrum and fungicidal activity. However,
considerable side effects limit its clinical utility. Echinocandins are
large lipopeptide molecules that inhibit the synthesis of 1,3-b-Dglucan,
a key component of the fungal cell wall. Three echinocandins
(caspofungin, micafungin and anidulafungin) have reached the market.
Caspofungin is also known as pneumocandin or MK-0991.
This compound was the first cell-wall-active antifungal approved as
a new injectable antifungal; this was in 2000.38 It irreversibly inhibits
1,3-b-D-glucan synthase, preventing the formation of glucan polymers
and disrupting the integrity of fungal cell walls.39 It is more active and
less toxic than amphotericin B and shows a broad spectrum of activity
against Candida (including fluconozole resistance), Aspergillus,
Histoplasma and P. carinii, the major cause of HIV death. Micafungin
is licensed for clinical use in Asian countries and in the US. This
compound exhibits extremely potent antifungal activity against
clinically important fungi, including Aspergillus and azole-resistant
Microbial drug discovery strains of Candida.
In animal studies, micafungin is as efficacious
as amphotericin B with respect to improvement of survival rate.
It is characterized by a linear pharmacokinetic profile and
substantially fewer toxic effects. Anidulafungin is currently licensed
in the US.40
Although several new antifungal drugs have been developed in the
past 6 years, some patients remain resistant to treatments. The main
reasons for this include intrinsic or acquired antifungal resistance,
organ dysfunction preventing the use of some agents and drug
interactions. In addition, some drugs penetrate poorly into sanctuary
sites, including the eye and urine, and others are associated with
considerable adverse events. However, there has been some progress.
Posaconazole is a new member of the triazole class of antifungals.
It has shown clinical efficacy in the treatment of oropharyngeal candidiasis
and has potential as a salvage therapy for invasive aspergillosis,
zygomycosis, cryptococcal meningitis and a variety of other fungal
infections. It is available as an oral suspension and has a favorable
toxicity profile. The wide spectrum of posaconazole activity in in vitro
studies, animal models and preliminary clinical studies suggests that it
represents an important addition to the antifungal armamentarium.
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