They use comparative biochemical differences between mammalian machineries
at one side and Archaea, Bacteria, lower Eukarya or
viral machineries at the other side. Antimicrobials may have a cidal
(killing) effect or a static (inhibitory) effect (useful to
induce active immunization against recurrent infections, but dangerous
in immunocompromised patients) on a range of microbes (antibiosis)
: sometimes a static compound may become a cidal compound just by increasing
its dose. The range of Bacteria or other microorganisms that is
affected by a certain antibiotic is expressed as its activity spectrum
/ range of activity.
broad spectrum : kill or inhibit a wide range of Gram-positive and
narrow spectrum : effective mainly against Gram-positive or Gram-negative
limited spectrum : effective against a single organism or disease
Please note sometimes antimicrobial chemotherapy
can be started before knowing the identity of the infecting microorganism,
using likelihood considerations (age, sex, endemic infections, immunological
status, localization of infection, ...). Parameters that influence antimicrobial choice are :
pharmacokinetics as determined by experimental in vivo studies
side effects (organ toxicity must be evaluated if individual already has
Antimicrobial therapy usually lasts > 5 days (> 5 months in prostatis)
to avoid cronicization of infection.
Antimicrobial associations are rare (obviously only sinergy
and indifference are useful !) and increase just the number of side effects
: so associations are used only if microbe undergoes rapid gene drift (e.g.
Antimicrobials can be classified according to source as follows :
antibiotics : low-molecular weight substances
that are produced as secondary metabolites by certain groups of microorganisms,
especially Streptomyces spp., Bacillus spp., and a few molds
(Penicillium and Cephalosporium) that are inhabitants of
soils : they are produced at the same time that the cells begin sporulation.
Antibiotics may require as many as 30 separate enzymatic steps to synthesize
: the maintenance of a substantial component of the bacterial genome leads
to the conclusion that the process (or molecule) is important, if not essential,
to the survival of these organisms in their natural habitat. Most of the
microorganisms that produce antibiotics are resistant to the action of
their own antibiotic, although the organisms are affected by other antibiotics,
and their antibiotic may be effective against closely-related strains [e.g.
: penicillin G].
semisynthetic antibiotic : an antimicrobial produced by the microbe
subsequently modified by the chemist to achieve desired properties.
disk diffusion test : Petri dishes
containing semisolid medium are homogeneously inoculated with a standardized
suspension of a microorganism. Antimicrobial-soaked disks are applied to
the agar surface (Kirby-Bauer, Barry, Ericsson, Stokes
and comparative methods). Following overnight incubation, the diameters
of the zones of inhibition or clearing surrounding the disks are measured.
Zone diameters are related to the minimal cydal concentration and interpreted
as sensitive (susceptible), indeterminate (or intermediate), or resistant.
scalar microdilution tests : in liquid or semisolid media. MIC90
and MIC / LC / IC50 (minimum inhibitory concentration
(mg/mL)) < MBC50 (minimum
mutant prevention concentration (MPC)
Microorganisms may have ...
phenotypical resistance to an antibiotic
innate or intrinsic resistance if ... :
persister : in bacteriology, a microorganism
that resists a generally toxic level of a drug but is not genetically resistant.
They tolerate but do not become resistant to antibiotics (neither grow
nor die in the presence of microbicidal antibiotics), preexist in a population
and their random switching between normal and slow-growing persister states
enables them to escape antibiotic killingref.
Persisters are largely responsible for the complete tolerance of biofilms
to killing by antibiotics : the number of persisters does not change in
lag or early exponential phase, and increases dramatically in mid-exponential
lack or possess a modified version of the target of the antibiotic
(e.g. : cell wall-building enzymes in cell wall-less Bacteria; PBP
certain antibiotics trigger the SOS response in bacteria, resulting
in shutdown of DNA replication and transient dormancy, enabling survival
of the antibiotic sensitive bacteria. The SOS response prevents damaged
DNA from being copied at cell division : it's common throughout the whole
plant, animal, bacterial worldref
possess an alternative pathway to create such metabolites
intracellular-acting antibiotic can't reach high intracellular concentrations
due to ..
production of an enzyme that inactivates the antibiotic (e.g. : b-lactamase,
inducible exoenzymes in Gram +ve, while constitutive or inducible endoenzymes
in the periplasmic space of Gram -ve Bacteria : Richmond classification
is based on substrate specificity, while Sykes-Matthew one is based
on genetic allocation; acetyltransferase, phosphotransferase, adenylyltransferase)
beta lactamases (ESBLs) are enzymes elaborated by bacteria, most often
but other Enterobacteriaceae
(e.g. Escherichia coli)
as well. These enzymes cleave, and, thereby, inactivate most penicillins
and cephalosporins. These have become common nosocomial pathogens in many
regions, and nosocomial outbreaks may occur. Treatment can be difficult,
but most isolates remain susceptible to the carbapenem antibiotics, such
In New York, where hospital-acquired infections with ESBL-producing bacilli
are fairly commonplace, an increasing number of these isolates are carbapenem-resistant
and many are amikacin-resistant. Polymyxin B has retained activity, however,
against most strains. Monitoring the number of cases of ESBL coliform infection
is important but is only one step in their overall control, which must
include control of overuse of antimicrobial drugs, aggressive, well-supported
infection control programs and the development of both rapid diagnostic
and new therapeutic methodologies.
production of a binding protein that inhibits normal uptake
lack of an effective transport system for the antibiotic (e.g. :
porin modification in Pseudomonas aeruginosa)
enhanced efflux mechanisms to pump the antibiotic out of the cell
acquired or extrinsic resistance is driven by 2 genetic processes
that create one of the conditions listed above :
vertical evolution : mutation (the mutation rate for most
bacterial genes is approximately 10-8/-9) and natural selection
horizontal evolution : horizontal or lateral gene transfer
(LGT) between strains and species through conjugation(since
usually develop their genes for drug resistance as transposons, these can
integrate themselves on R plasmids
: so often resistance to more than one antimicrobial is acquired), transductionor
Not only is there a problem in finding new antibiotics to fight old diseases
(because resistant strains of Bacteria have emerged), there is a
parallel problem to find new antibiotics to fight new diseases.
tolerance to an antibiotic, a temporary condition due to environmental
conditions or growth phase, causing higher MBC50 but same MIC50.
Hata phenomenon : increase in severity of an infectious disease
when a small dose of a chemotherapeutical remedy is given.
microbicide : an agent that destroys microbes.
The ideal vaginal microbicide must have in vivo activity against HIV-1
and other STD pathogens as well as a differential effect on the viability
of human cells and tissues encountered during use as a topical agent. On
the one hand, the ideal agent should be effective against incoming cells
infected by STD pathogens. Specifically, microbicides that effectively
reduce or eliminate the risk of HIV-1 transmission must kill HIV-1-infected
immune cells (T cells, monocytes, and macrophages) as well as inactivate
cell-free virions. On the other hand, topical microbicides must have minimal
or no impact on the viability, function, and structural integrity of the
vaginal and cervical epithelium. Although preclinical, in vitro assays
of immune and epithelial cell sensitivity to candidate microbicides are
necessary steps in the development of a potential microbicide, in vitro
assays may fail to predict a compound's in vivo activityref1,
One approach previously thought to be a necessary prerequisite for defining
the fidelity of in vitro assays was the use of tissues or cells of primary
human origin to test candidate microbicidesref1,
However, compared to available human immune and epithelial cell lines,
primary tissues and cells are more difficult to acquire and isolate, less
convenient and more expensive to maintain, potentially contaminated with
unwanted cell populations, and prone to donor-specific variationref.
nonoxynol-9 (N-9) (also a spermicide)
: intravaginal N-9 is found in the uterus shortly after its insertion.
Exposure of the female upper reproductive tract to N-9 may alter epithelial
integrity, thereby increasing HIV-1
transmission risk. It is thought to attack and weaken vaginal cell walls,
as well as the target virusref.
N-9 has in vitro activity against several STD pathogens, including
but cannot be classified as broadly effective, since it has no activity
against nonenveloped viruses such as HPVref.
vivo effectiveness of N-9 as a microbicide is unclear. Clinical studies
have provided conflicting indications of N-9 effectiveness against transmission
of HIV-1 and other STD pathogensref1,
Results from human and animal studies also indicate a narrow margin between
N-9 effectiveness and safetyref,
as well as associations between N-9 use and vaginal irritation, inflammation,
tissue infiltration by host immune cells, and changes in vaginal floraref1,
These adverse effects may increase the risk for HIV-1 transmission during
sexual intercourse. N-9 is 10-fold more toxic than C31G or SDS in long-term
experiments using primary vaginal keratinocytes. This observation may be
particularly relevant to considerations of long-term toxicity during N-9
use. A clinical study of N-9 retention following vaginal insertion of a
film containing N-9 demonstrated that levels of N-9 recovered by vaginal
lavage remained constant for up to 2 h after product insertion and decreased
to under 50% after 4 href.
A similar report described levels of retention between 19 and 7% after
2 h, detectable levels of N-9 as long as 24 h after insertion, and levels
of retention dependent on the contraceptive formulationref.
C31G is an equimolar mixture of 2 amphoteric,
surface-active molecules: a C14 alkyl amine oxide and a C16 alkyl betaine.
C31G is a broad-spectrum antimicrobial and spermicidal agentref1,
However, like N-9, C31G has no activity against HPVref,
a sexually transmitted virus that has a direct causative role in the development
of human cervical cancer. It has broad-spectrum antibacterial and antiviral
including HIV infection : glyminox (Savvy™; source : Biosyn, Inc.)
is a 1.2% vaginal gel formulation of C31G as a potential contraceptive
and for the potential prevention of transmission of sexually transmitted
diseases. In March 2002, glyminox was in phase II/III trials for Chlamydia
treatment and as a contraceptive, and in phase II trials for HSV sheddingref.
sodium dodecyl sulfate (SDS)
/ sodium lauryl sulfate : has in vitro activity against STD
pathogens, including HIV-1 and HSV-2ref1,
It is an attractive candidate microbicide due to its lower cytotoxicityref1,
and ability to inactivate HPVsref.
SDS, an alkyl sulfate commonly used in research applications and in commercially
available personal hygiene products, is significantly less cytotoxic than
either N-9 or C31G and is effective against HIV-1, HSV-2, and, importantly,
papillomaviruses from several species, including humansref1,