IMIDAZOL

Imidazole analogues has generated keen interest over the years due to their wide range of
biological properties including antimicrobial, anti-inflammatory, analgesic, antiulcerative,
histamine H3 antagonist, antioxidant, farnesyltransferase and geranylgeranyltransferase-I
inhibitor, antitumoral, antiparasitic, antiprotozoal, and antidiabetic activities 1

Vijesh et al. carried out the in vitro antibacterial activity of newly synthesized compounds 1a–d and 2a–j.
Escherichia coli, Staphylococcus aureus, Bacillus subtilis, Salmonella typhimvrium, Clostridium
perfringens, and Pseudomonas aeruginosa were used to investigate the activity. The antibacterial
screening revealed that some of the tested compounds showed good inhibition against various tested
microbial strains. 1c showed excellent activity against P. aeruginosa and C. perfringens compared to
standard drug streptomycin .2

Mechanism of Action

Imidazoles act via different mechanisms. According to one study, nitroimidazoles enter in to
the cell by passive diffusion where it undergoes reduction to yield nitro radical anion. This
anion oxidizes the DNA which results in breakage of DNA strand and causes cell death.

Nitric oxide (NO) is released by macrophages and otherimmune cells to poison and help eliminate
infectious microbes,parasites, and tumor cells (12, 27, 41). Diverse life forms pro-tect against NO
toxicity by expressing NO-metabolizing en-zymes. NO dioxygenases (NODs) (EC 1.14.12.17) convert
NOto NO3(equation 1), while in some organisms NO reductases(NORs) (EC 1.7.99.7) reduce NO to N2O
(equation 2) (18, 39,64). NODs utilize O2for NO detoxification, whereas NORsscavenge and detoxify
NO under anaerobic conditions andsupplement NOD under the microaerobic conditions found
ininfections.
Mechanism of

action cephalosporin

Cephalosporins induce their antimicrobial effect byinhibiting the integration of bacterial

peptidoglycan.Individual peptidoglycan units are synthesized in thecytoplasm of the
bacterial cell and are transportedacross the cytoplasmic membrane where they are in-
serted by peptidase enzymes into a crosslinked latticethat forms the structural support of
the bacterial cellwall. The peptidase enzymes present in the outer cytoplasmic membrane
are referred to as penicillin-binding proteins and represent the target sites forantibacterial
action of cephalosporins and otherb-lactam antibiotics. Cephalosporins are
activeinvitroagainst many gram-positive aerobic bacteriaand some gram-negative aerobic
bacteria. There aresubstantial differences among the cephalosporins intheir spectra of
activity as well as levels of activityagainstsusceptiblebacteria.Later-
generationcephalosporins also are used in the later stages oflivestock raising for adding
weight.
The human immune system is made up of leukocytes (white blood cells [WBC]), which include
neutrophils, eosinophils, basophils, lymphocytes, monocytes, macrophages, and dendritic cells.
These cells function through two distinct methods of cellular response. The first bodily response
to a foreign entity (bacterial, fungal, viral, or parasitic) is through the innate immune system.
This system involves a nonspecific response to an invading pathogen that is predominately
carried out by phagocytes, including macrophages, natural killer cells (NK cells), and
neutrophils.5 Along with the innate immune system, the body also has adaptive immunity. This
system mainly comprises lymphocytes, including T cells and B cells, both of which are produced
in response to a specific antigen. Such a response produces immune memory. When the antigen
is seen again in the body, the T and B cells will target that antigen and produce a more efficient
immune response.5

Normal levels of leukocytes can differ with ethnic background.6,7 One study has shown that the
WBC and absolute neutrophil count (ANC) can range drastically between African American,
Caucasian, and Mexican American populations. A normal WBC range for an African American
man (>18 years of age) can be between 3.1 and 9.9 (x103/µL) with an ANC between 1.3 and 6.6.
Caucasian and Mexican American men show a WBC range between 4.1 and 11.4 with an ANC
between 2.1 and 8.0. Though these levels are different, African American men do not appear to
have an increased risk of infection.6

Neutrophils are the most abundant WBCs. They are produced in the bone marrow at a rate of
0.85 to 1.63 x 109 cells/kg/day (∼1011 cells/day) and remain for 4 to 6 days. At this point, the
production rate overcomes the high turnover, and concentration reaches 5.59 x 109 cells/kg. The
cells then travel to the blood at a rate of 109 cells/kg/day. An individual cell takes 6.6 days to
reach the bloodstream, where the turnover rate is 0.87 x 109 cells/kg/day. Each neutrophil has a
half-life in the blood of 6 to 8 hours. Under noninflammatory conditions, both neutrophil
production and migration out of the bone marrow are controlled by granulocyte colony-
stimulating factor (G-CSF).8

This neutrophil timeline may be altered by both neutropenia and infection. When an infection is
initially identified by the immune system, cytokine release signals for neutrophils and
macrophages circulating in the plasma to migrate to the area of infection.9 In experimental
models, this resulted in an initial decrease in plasma concentrations of neutrophils and
macrophages that reached their nadir on Day 1 Postinoculation.9,10 The same cytokines that cause
circulating neutrophils to migrate to the area of infection then cause the bone marrow to release
neutrophils, which migrate to the affected site. This increase in circulating neutrophils offsets the
initial decrease seen in the first stage of infection. Concentrations rise in response to increasing
bacteria counts, peaking at four days postinfection. Reduction in neutrophil release from bone
marrow occurs as the bacterial load from the initial infection begins to decrease. This generally
occurs seven days after the onset of infection.9
Transit time is expected to be reduced in patients with infection. This was illustrated by the
canine model provided by Marsh et al.11 Here, the granulocyte pool in the marrow becomes
elevated and the transit time to the blood is reduced by two days. It appears that this reduced
transit time is temporary and is followed by a period of normal to elevated transit time. It is
understood that the process begins with release of the cells from the marrow into the circulating
granulocyte pool (CGP) in the bloodstream. Neutrophils leave the bloodstream and migrate to
the tissue at the site of infection. In order to do so, the marginal granulocyte pool (MGP) must
increase. The CGP cannot be restored until bone marrow stores are replenished and released
from the bone marrow. In both subacute and chronic infection, CGP is more frequently elevated
than is MGP.

Antibiotic treatment has the potential to affect the normal physiological actions of the innate
immune system. Depending on the drug this effect can be beneficial or detrimental to the
immune system and health of the infected host. Macrolide antibiotics decrease cytokine release
and in turn decrease the migration of neutrophils to sites of infection. They have an immune-
modulating effect by inhibiting the synthesis of pro-inflammatory cytokines and chemokines
while simultaneously facilitating the release of anti-inflammatory cytokines. Macrolides may
also exert a direct effect on neutrophils through alterations in rates of oxidative burst and
apoptosis.13 By facilitating the onset of apoptosis, cell death is produced without a subsequent
release in inflammatory mediators. This prevents the death of surrounding neutrophils.14,15 Beta-
lactam antibiotics have shown an effect on decreasing total neutrophil concentration in the
plasma leading to decreased WBC count and neutropenia. This is thought to be caused by a
combination of decreased granulopoiesis and induction of antibodies against the formation of
haptens on neutrophils.16–18 Vancomycin has also been shown to cause neutropenia in patients
due to the formation of hapten molecules on neutrophils.19,20 Further studies are necessary to
evaluate how great of a risk is actually associated with these antibiotics.

Beta-lactams. Penicillins and other beta-lactam antibiotics have been previously associated with
reductions in ANC/WBC resulting in neutropenia. A review study by Scheetz18 included six case
reports and three cohort studies of piperacillin-induced neutropenia.18 Of the six case reports,
three included patients who became neutropenic while receiving piperacillin and three who
developed neutropenia secondary to therapy with a combination of piperacillin and tazobactam.
Each of the six cases of neutropenia occurred after at least 15 days of therapy, though the
average dose was not specified. Review of the cohort studies determined that rates of
neutropenia were dependent upon both dose and duration of therapy.18 Additionally, Neftel17
examined the relationship between beta-lactam antibiotics and neutropenia. In the cases
evaluated, the majority of treatments that resulted in neutropenia were regimens that lasted more
than 10 days. The mean duration of therapy was 23.2 days; however, results differed between the
different antibiotics.17 Within the beta-lactam class, cephalosporin drugs were as much as 25
times more potent than penicillins in decreasing the amount of marrow growth.17

Data were also gathered regarding the effects beta-lactam antibiotics had on normal bone
marrow cultures. Initial bone marrow colony formation decreased 90 to 100 percent when
cultures were grown in the environment of penicillins and cephalosporins as compared to growth
in the presence of placebo. The drugs were then washed from the bone marrow cultures and the
cells recovered with as much viability as marrow exposed to placebo.
The formation of hapten molecules on the cell surface is also responsible for neutropenia.7,16 A
hapten is formed when a molecule, in this case a drug, binds to a protein on the surface of a
cell.30 The immune system reads the hapten as a foreign protein and produces an antibody against
the hapten. The antibody binds in a similar way as it would to a bacterial or viral structure, and
induces an immune response.30–32 Unlike granulopoiesis, the formation of hapten molecules on
cell surfaces is not time-related and can occur within hours to days from the initiation of the
drug.7 The incidence of neutropenia is reversible upon discontinuation of the offending agent.