الفهرس 
Classification of antibioticsOnly 14 pages are availabe for public view
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Abstract
This study was aimed to high light the problem of antibiotics resistance and its possible relation to individual pharmacogenetics.
Antibiotics have been used for more than 50 years and are the cornerstone of infectious disease treatment; in addition, these low-molecular-weight bioactive compounds have been applied to many other therapeutic purposes (Davies, 2006). Use of antibiotics impacts both the bacterial ecology and the host at multiple levels, both advantageously and deleteriously. Since serious bacterial infection can lead to death in the absence of antibiotic therapy, antibiotics remain a necessary weapon for maintaining good health (Davison & Barrett, 2003).
Antibiotics are commonly classified based on their mechanism of action, chemical structure, or spectrum of activity. Mostly target bacterial functions or growth processes. (Calderon &Sabundayo, 2007). The widespread use of antibiotics both inside and outside of medicine is playing a significant role in the emergence of resistant bacteria (Goossens et al., 2005). Although there were low levels of pre-existing antibiotic-resistant bacteria before the widespread use of antiotics (Caldwell & Lindberg, 2011) evolutionary pressure from their use has played a role in the development of multidrug resistance varieties and the spread of resistance between bacterial species (Hawkey & Jones, 2009).
The volume of antibiotic prescribed is the major factor in increasing rates of bacterial resistance rather than compliance with antibiotics (Pechère, 2001). Single dose of antibiotics leads to a greater risk of resistant organisms to that antibiotic in the person for up to a year (Ceire et al, 2010).
Antibiotic administration affects not only the intended pathogen but also the normal flora. This commensal flora can then act as a reservoir of resistance and pass resistant genes to potentially pathogenic bacteria (Malhotra et al., 2007).
Antibiotic exposure allows bacteria to develop novel mechanisms for overcoming the effects of antimicrobials. The main mechanisms of antibiotic resistance are enzymatic inactivation, decreased uptake, increased removal, and alteration of target sites (DeBellis & Zdanawicz, 2009). These mechanisms are not mutually exclusive, and resistant bacteria most likely use multiple mechanisms concurrently (Thomas et al., 2001).
Strategies to limit antimicrobial resistance are based on four basic principles, which are containment of resistant species, infection prevention, infection eradication, and optimizing antibiotic utilization. Optimizing antibiotic utilization is an important and promising means of limiting the spread of antibiotic resistance. (Raymond et al., 2007).
Last decade saw an alarming increase in antibiotic resistance in infections, with more than 13 million deaths per year from infections. Presently, pharmacogenomics with basic research is revealing new antimicrobial peptides and is applying old drugs in new ways to break resistance(Dandekar &Dandekar, 2010).
Pharmacogenomics is the whole genome application of pharmacogenetics which deals with the influence of genetic variation on drug response in patients by correlating gene expression or single-nucleotide polymorphisms with a drug’s efficacy or toxicity (Wang, 2010).
Pharmacogenetics is the study of variability in drug response due to genetic factors, which are mainly inherited in conjunction with environmental factors, usually determine drug responses. The identification of genetic factors that influence drug absorption, metabolism, and action at the receptor level should allow for individualized therapy; this could optimize drug efficacy and minimize toxicity profiles in a given population (Mancinelli et al., 2000).
I-Genes affecting drug metabolism:
One of the major causes of interindividual variation of drug effects is genetic variation of drug metabolism. Genetic polymorphisms of drug-metabolizing enzymes give rise to distinct subgroups in the population that differ in their ability to perform certain drug biotransformation reactions. Polymorphisms are generated by mutations in the genes for these enzymes, which cause decreased, increased, or absent enzyme expression or activity by multiple molecular mechanisms. Moreover, the variant alleles exist in the population at relatively high frequency. Genetic polymorphisms have been described for most drug metabolizing enzymes (Meyer & Zanger, 1997).
1-Acetylation genes
These genes are located on chromosome 8, and share 87% coding sequence homology. It is located in cytosolic fraction of liver and many other tissues of most mammalian species (Vatsis et al., 2000).
NAT2 is a xenobiotic metabolising enzyme that provides a major route of detoxification of drugs such as isoniazid , hydralazine and endralazine , a number of sulphonamides(Kawamura et al., 2005), procainamide, aminoglutethim, nitrazepam and the anti inflammatory drug dapsone (Ginsberg et al., 2009 & Butcher et al., 2002).
2- Cytochrome P450 dependent enzyme system
CYP450 superfamily is a large and diverse group of enzymes that catalyze the oxidation of organic substances. They are the major enzymes involved in drug metabolism and bioactivation, accounting for about 75% of the total number of different metabolic reactions. CYP450 enzymes, found primarily in the liver, are involved in the metabolism of most medications; the most important of these enzymes are CYP2D6, CYP2C9, CYP2C19 and CYP3A4 (Guengerich, 2008).
II-Genes affecting antibiotics metabolism
4- N-Acetyltransferase 2 gene (NAT2)
The genetic polymorphism of human NAT2 divides the human population into groups with rapid, intermediate and slow acetylator status (Brocvielle et al., 2003). Adverse reactions with isoniazid, which include nausea, drug-induced hepatitis, peripheral neuropathy, and sideroblastic anemia, are associated more often with a slow NAT2 acetylator phenotype. These individuals may require a lower dose to avoid adverse reactions (Chen et al., 2006).
5- Glucose-6-Phosphate Dehydrogenase Gene (G6PD)
G6PD deficiency results in hemolysis in individuals when exposed to certain antimicrobial agents, such as dapsone, primaquine, and nitrofurantoin. These drugs should be avoided in those known to be deficient in G6PD, and it is advisable to test for this predisposition in patients who might have a higher risk of G6PD deficiency (eg, African Americans) before prescribing these agents (Leekha et al., 2010).
6- Voltage gated Potassium channel gene ( Kv channels) Macrolides and fluoroquinoles are widely prescribed for treatment of infections and are traditionally known to cause Q-T interval prolongation and are at risk to induce Torsade de Pointes (TdP) that represent one of the most dangerous effects with these drugs. Recently, erythromycin was found to induce TdP, with relative high frequency, even if administered by oral route. A recent trial conclude that short term clarithromycin in patients with stable coronary heart disease may significantly cause higher cardiovascular mortality (Pannacci et al., 2008).
III-Drug biotransformation
Biotransformation is the process whereby a substance is changed from one chemical to another (transformed) by a chemical reaction within the body (Monosson, 2007). Drug metabolizing enzymes are a diverse group of proteins that are responsible for metabolizing a vast array of xenobiotic chemicals, including drugs, carcinogens, pesticides, pollutants, and food toxicants, as well as endogenous compounds, such as steroids, prostaglandins, and bile acids (Coon 2005, Brown et al., 2008, Guengerich & Rendic, 2010).
c- Phase I biotransformation reaction:
Phase I reactions are broadly grouped into three categories, oxidation, reduction, and hydrolysis. As most small molecule drugs are lipophilic in nature, drug metabolism converts these hydrophobic compounds into more water soluble compounds that can be excreted. Typically, oxidation is the most common phase I reaction. The hepatic cytochrome P450 system is the most important of the phase I oxidation systems (Parkinson &Ogilvie, 2008 ).
d- Phase II biotransformation reaction
Phase II enzymes play also an important role in the biotransformation of endogenous compounds and xenobiotics to more easily excretable forms as well as in the metabolic inactivation of pharmacologically active substances. The purpose of phase II biotransformation is to perform conjugating reactions. These include glucuronidation, sulfation, methylation, acetylation, glutathione and amino acid conjugation. In general, the respective conjugates are more hydrophilic than the parent compounds (Jancova et al., 2010).
IV-Application of pharmacogenetics in general pediatric therapy:
pharmacogenetics have been used in childhood ALL for several years, the only genetic variants routinely tested today are in the gene encoding TPMT. TPMT is an enzyme involved in the metabolism of 6-MP; it catalyses the conversion of 6-MP to the less cell toxic 6-methyl mercaptopurine (Wesolowska et al., 2011).
The potential benefits of pharmacogenetics are:
a- Development of drugs that maximize therapeutic effects but decrease damage to nearby healthy cells.
b- Prescription of drugs based on a patient’s genetic profile versus trial and error decreasing the likelihood of adverse reactions.
c- More accurate methods of determining dosages.
d- Development of vaccines made of genetic material could activate the immune system to have all the benefits of existing vaccines but with reduced risks of infections (Niazi & Riaz, 2006).
Individualization of drug dosage
Individualized medicine not only allows the possibility of finding new uses of a known drug, but also allows the correlation of drug dosage to specific patients with a particular genetic makeup. If a correlation can be made, then genetic testing may be used to reveal which patients are suitable to take the particular drug and at what dosage allowing for the elimination of unsuitable test subjects during clinical trials (Micheline & Denis, 2007).