Abstract
There are two major classes of bacteria, which are identified by the response of the bacterial cell wall to a staining procedure using with gentian violet dye. This procedure was developed more than 100 years ago by a Danish physician, Hans C.J. Gram. The bacteria that are exposed to the dye and retain it are gram-positive; those that do not, gram-negative. Thus, "gram," in this context, has nothing to do with a measurement of weight.
The penetration or non-penetration of the stain depends on the structure of the bacterial cell walls. Gram-negative bacteria have a thick outer membrane that coats the walls.

Introduction
Bacteria can rapidly change their genetic material, which allows the development of antimicrobial resistance. They accomplish this in two main ways--first by their rapid multiplication and high mutation rate, and second by their ability to acquire genetic material from external sources.
Antibiotics are unique among therapeutic agents in that their desired effect is directed at an invading microorganism, rather than at a physiologic process of the host. Antibiotic resistance, a major adverse effect of antibiotic usage, is an effect on the microbial environment rather than a direct effect on the host.
Because microorganisms leave an individual host and enter the community, the emergence of resistance within the host will ultimately affect the community.
We have depended on the pharmaceutical industry to continue to provide us with new antimicrobial agents to which bacteria have not developed resistance. This may be an unrealistic expectation. In fact, we may be entering the "postantibiotic era."

Gram Negative Bacteria
The Enterobacteriaceae and nonfermenters such as Pseudomonas aeruginosa and Acinetobacter sp account for a significant proportion of bacterial isolates from clinical specimens, especially those obtained from hospitalized patients. Many of these bacteria exhibit resistance to multiple classes of antimicrobial agents as a result of all the different mechanisms discussed. Although a major problem in hospitalized patients, this is by no means a problem confined to hospitals, because bacteria colonizing hospitalized patients are carried to the community at large. Furthermore, bacteria with the potential for causing epidemic disease, especially in countries where sanitation is poor, have shown significant antibiotic resistance. These include Shigella sp resistant to ampicillin and to trimethoprim/sulfamethoxazole; Salmonella typhi resistant to ampicillin, chloramphenicol, and trimethoprim/sulfamethoxazole; and nontyphoid salmonellae resistant to multiple antibiotics.

Haemophilus influenzae
The capsular serotype b (HIB) of this species was the most common cause of bacterial meningitis in children in the United States before the widespread use of HIB vaccines. The nonencapsulated (nontypeable) strains of this organism are still common causes of otitis media and acute exacerbations of respiratory illness in individuals with chronic bronchitis. In the 1970s ampicillin resistance mediated by TEM-1 beta-lactamase emerged, so that chloramphenicol became the primary treatment of H influenzae meningitis. Chloramphenicol resistance emerged in the late 1970s; however, by this time it became largely replaced by second- and then third-generation cephalosporins as therapy for systemic H influenzae infections. In the same manner as this organism acquired the gene for TEM-1 beta-lactamase, it could acquire the gene for TEM-3 or for other broad-spectrum beta-lactamases, which would render it resistant to third-generation cephalosporins.

Neisseria gonorrhoeae
This organism is spread rapidly by sexual contact. As a result of its acquisition of the gene for TEM-1 beta-lactamase production, penicillin therapy is no longer reliable. Tetracycline resistance is also widespread. Currently, the third-generation cephalosporin ceftriaxone is the recommended treatment of infections caused by this organism. Acquisition of a gene mediating resistance to this agent, eg, TEM-3 beta-lactamase, would make treatment of patients infected with this organism more difficult.

Neisseria meningitidis
This is one of the most feared of bacteria because of its ability to cause meningitis and fulminating septicemia. Penicillin has been the treatment of meningococcal infections for many years. Recently, strains of decreased susceptibility to penicillin have been recognized. The mechanism of resistance in these strains is a decrease in the affinity of penicillin for PBP 2, resulting from genetic recombinations. The concerns relating to H influenzae and to N gonorrhoeae also apply to N meningitidis.

Barrier to Entry
This constitutes an important mechanism of resistance in gram-negative bacteria. Decreased entry of a drug into the organism, in addition to alteration or destruction of whatever amount of drug is able to enter, can result in high degrees of resistance. The entry of antibiotics as well as other complex molecules into gram-negative bacteria requires a pathway through the lipopolysaccharide outer membrane. Protein channels called porins provide this pathway. The ability of molecules to pass through these channels is influenced by their size, shape, and electrical charge. Decreased entry of antibiotic into the bacterial cell is not important in gram-positive bacteria because they lack a lipopolysaccharide outer membrane. Although the peptidoglycan layer of gram-positive bacteria is thicker than that of gram-negative, it does not pose a significant barrier to antibiotic entry.

Rapid Extrusion (Efflux Mechanism)
This is an energy-dependent mechanism whereby a bacterium can pump out an antibiotic from its interior so that it does not accumulate and cannot exert its antibacterial effect. This is best recognized as a mechanism of tetracycline resistance, but has also been demonstrated as one mechanism of resistance to macrolides, chloramphenicol, and fluoroquinolones.

Enzymatic Modification of the Drug
This is the most important mechanism of resistance to beta-lactams, aminoglycosides, and chloramphenicol. The enzymes are often plasmid-encoded, but they may be chromosome-encoded.
beta-lactam-modifying enzymes. Of the three types of these enzymes, namely beta-lactamase, acylase, and esterase, beta-lactamase is by far the most important. These enzymes hydrolyze the beta-lactam bond of penicillins and cephalosporins, rendering the drugs inactive. There are many different beta-lactamases. No beta-lactam antibiotic is immune to the effects of every beta-lactamase. As a new beta-lactam agent enters clinical usage, one can expect a beta-lactamase to appear that can hydrolyze it. beta-lactamases may be primarily penicillinases or cephalosporinases, broad-spectrum or narrow-spectrum, chromosome-encoded or plasmid-encoded, and constitutive (ie, produced at all times) or inducible (ie, produced only when stimulated to do so). Some gram-positive bacteria produce beta-lactamase, in which case it is excreted into the external environment. These include Staphylococcus aureus, coagulase-negative staphylococci, Enterococcus faecalis, and Bacillus cereus, all of whose enzymes are primarily penicillinases, as well as Nocardia sp and Mycobacterium sp. Many gram-negative bacteria produce this enzyme, which is excreted into the periplasmic space. These bacteria include all members of the Enterobacteriaceae, Pseudomonas sp, Xanthomonas maltophilia, Acinetobacter sp, Moraxella catarrhalis, Haemophilus influenzae, Legionella sp, Neisseria gonorrhoeae, and Bacteroides sp.

Of particular note are two groups of broad-spectrum beta-lactamases produced by some gram-negative bacteria. The first are the broad-spectrum, inducible, chromosome-encoded beta-lactamases of Enterobacter sp, Citrobacter sp, Serratia sp, Morganella morganii, and Pseudomonas aeruginosa. The genes for these beta-lactamases are repressed, and induction occurs when the organism is exposed to certain beta-lactam drugs (eg, cefotaxime) that derepress the gene. However, the gene may become stably derepressed, resulting in constitutive production of large quantifies of the enzyme. These enzymes are active against all beta-lactams except imipenem. The second group is composed of plasmid-encoded broad-spectrum beta-lactamases active against the newer cephalosporins, eg, cefotaxime and ceftazidime. These are derived from mutations of genes coding for more narrow-spectrum beta-lactamases. Mutations of one or two nucleotides can result in major changes in the spectrum of activity of the enzyme.

Aminoglycoside-modifying enzymes. Amino-glycosides have several amino and hydroxyl side groups that are susceptible to enzymatic modification. The responsible enzymes, namely aminoglycoside acetyltransferases, phosphotransferases, and adenyltransferases, are specific for the amino or hydroxyl groups at specific sites. They may be active at analogous sites on different aminoglycosides, result-mg m cross-resistance between drugs.

Chloramphenicol acetyltransferase results in inactivation of this drug.

Means By Which Bacteria Become Resistant To Antibiotics
Antibiotic resistance, like any other phenotypic characteristic, is determined by the bacterial genome. This may change as a result of mutation or by acquisition of new genetic material. Bacteria multiply rapidly, some having generation times as short as 30 minutes. They have genetic mutations every 106 to 109 divisions, resulting in the frequent opportunity for a mutation and thus for antibiotic resistance. The acquisition of new genetic material occurs by three mechanisms. The first is conjugation, in which a plasmid is passed from one organism to another through a pilus. This can occur not only between individual bacteria of the same strain or species, but also between bacteria of different genera or families. For example, the TEM-1 gene encoding for penicillinase production emerged initially in Escherichia coli and spread to Haemophilus influenzae and to Neisseria gonorrhoeae, resulting in penicillin and ampicillin resistance in these organisms. This method of spread of antibiotic resistance genes is also called "infectious drug resistance." The spread of genes coding for antibiotic resistance is facilitated by mobile genetic elements called transposons, which can move from plasmids to the bacterial chromosome, and in the reverse direction t. The second mechanism by which bacteria acquire new genetic material is transformation, in which DNA is assimilated from the external environment. The third is transduction, in which genetic material is acquired from an infecting bacteriophage.

Mechanism By Which Resistant Bacteria Spread
Antibiotic resistance spreads both as a result of resistance genes spreading (infectious drug resistance) and, of much greater importance, as a result of resistant bacteria spreading. The latter occurs in the same way as susceptible bacteria spread, from individual to individual. This is particularly important within hospitals, where antibiotic-resistant bacteria are more prevalent than in the outside community and where bacterial spread from patient to patient is facilitated by carriage on the hands of staff. However, in this era of rapid international travel, resistant bacteria can be readily spread around the world?

The Role Of Physicians In Spreading Antibiotic Resistance
Physicians play an important role in increasing the prevalence of antibiotic-resistant bacteria by spreading bacteria from patient to patient and by their prescribing practices regarding antibiotics. We often prescribe antibiotics for patients who might have a bacterial infection that could become worse if untreated.