What Is Antibiotic?

An antibiotic is a drug that kills or slows the growth of bacteria. Antibiotics are one class of "antimicrobials", a larger group which also includes anti-viral, anti-fungal, and anti-parasitic drugs. They are relatively harmless to the host, and therefore can be used to treat infection. The term originally described only those formulations derived from living organisms, but is now applied also to synthetic antimicrobials, such as the sulfonamides.

Unlike previous treatments for infections, which included poisons such as strychnine, antibiotics were labelled "magic bullets": drugs which targeted disease without harming the host. Antibiotics are not effective in viral, fungal and other nonbacterial infections, and individual antibiotics vary widely in their effectiveness on various types of bacteria. Some specific antibiotics target either gram-negative or gram-positive bacteria, and others are more wide-spectrum antibiotics. The effectiveness of individual antibiotics varies with the location of the infection and the ability of the antibiotic to reach this site. Oral antibiotics are the simplest approach when effective, with intravenous antibiotics reserved for more serious cases. Antibiotics may sometimes be administered topically, as with eyedrops or ointments.

Following earlier experiments that had demonstrated interesting anti-bacterial effects from various bacterial secretions, the German scientist E. de Freudenreich in 1888 isolated a bacterial secretion and noted its antibacterial properties. Pyocyanase, secreted by Bacillus pyocyaneus, retarded the growth of other bacteria in situ and was toxic to many disease-causing bacteria. Unfortunately, pyocyanase's own toxicity and unstable character prevented its use as an effective, safe antibiotic within the human body.

The first effective antibiotic discovered was penicillin. French physician Ernest Duchesne noted in his 1896 thesis that certain Penicillium molds killed bacteria. Duchesne died within a few years, and his research was forgotten for a generation, until an accident intervened. Alexander Fleming had been culturing bacteria on agar plates, one of which was ruined by an accidental fungal contamination. Rather than discarding the contaminated plate, Fleming noticed a clear zone surrounding the colony of mold. Having previously studied the ability of the enzyme lysozyme to kill bacteria, Fleming realized that the mold was secreting something that stopped bacterial growth. He knew that this substance might have enormous utility to medicine. Although he was unable to purify the compound (the beta-lactam ring in the penicillin molecule was not stable under the purification methods he tried), he reported it in the scientific literature. Since the mold was of the genus Penicillium, he named this compound penicillin.

This USPS stamps notes that during the 1940s, the improvement of antibiotics saved lives the world over.In the 1930s German scientists investigated the antibacterial properties of certain dyes. One of these was a sulfonamide, prontosil, which was used to treat infections in humans, where its effect was found to be due to its conversion in the host to the active form, sulfanilimide. By today's more broad definition, this would likely qualify as the first successful use of an oral antibiotic. During the same era, Rene Dubos isolated tyrothricin, an antibiotic used topically for skin infections, from soil bacteria.

With the increased need for treating wound infections in World War II, resources were poured into investigating and purifying penicillin, and a team led by Howard Walter Florey succeeded in producing usable quantities of the purified active ingredient which were quickly tested on clinical cases. Physicians were exhilarated at the rapid and reliable cure of conditions which had, until then, been difficult to treat, terrible to endure, and frequently fatal. Observation of other species of mold and other organisms revealed a hitherto unknown level of chemical warfare being carried out against bacteria. New antibiotics were rapidly discovered and came into widespread use, and a new era of research into the possibility of similarly "magic" chemotherapeutic cures for other diseases eventually led to successes in the field of cancer chemotherapy.

The discovery of antibiotics, along with anesthesia and the adoption of hygienic practices by physicians (for example, washing hands and using sterilized instruments) revolutionized medicine. It has been said that this is the greatest advance in health since modern sanitation. People in developed countries now find it hard to imagine that a simple scratch once always carried the risk of infection and death.

Classes

There are many way to classify antibiotics.

One such classification is by chemical structure:

aminoglycosides
    amikacin
    dibekacin
    gentamicin
    kanamycin
    neomycin
    netilmicin
    paromomycin
    sisomycin
    streptomycin
    tobramycin
beta-lactam ring antibiotics
    carbapenems
        ertapenem
        imipenem
        meropenem
    cephalosporins and cephamycins
        cephalexin
        cefuroxime
        cefadroxil
        ceftazidime
    monocyclic beta-lactams
    penicillins
glycopeptide antibiotics
    vancomycin
    teicoplanin
    ramoplanin
    decaplanin
macrolides
    erythromycin
    azithromycin
    clarithromycin
    roxithromycin
    ketolides
        telithromycin
oxazolidinones
    linezolid
    quinupristin/dalfopristin
polymyxins
    polymyxin B
    colistin
quinolones (fluoroquinolones)
    nalidixic acid
    ciprofloxacin (Cipro)
    ofloxacin
    norfloxacin (Norflox)
    levofloxacin (Levaquin)
    trovafloxacin (Trovan)
streptogramins
sulfonamides
tetracyclines
    doxycycline
    oxytetracycline
    chlortetracycline
other important antibiotics:
    chloramphenicol
    clindamycin
    fusidic acid
    trimethoprim

Another such classification is by their mechanism of action (that is, the mechanism by which they selectively poison bacterial cells):

Antibiotics can also be classified by the organisms against which they are effective, and by the type of infection in which they are useful, which depends on the sensitivities of the organisms that most commonly cause the infection and the concentration of antibiotic obtainable in the affected tissue.

Side effects

Side effects range from slight headache to a major allergic reaction. One of the more common side effects is diarrhea, which results from the antibiotic disrupting the balance of intestinal flora, the "good bacteria" that dwell inside the human digestive system. Other side effects can result from interaction between the antibiotic and other drugs, such as elevated risk of tendon damage from administration of a quinolone antibiotic with a systemic corticosteroid.

Antibiotic misuse

Common forms of antibiotic misuse include taking an inappropriate antibiotic, in particular the use of antibacterials for viral infections like the common cold, and failure to take the entire prescribed course of the antibiotic, usually because the patient feels better before the infecting organism is completely eradicated. In addition to treatment failure, these practices can result in antibiotic resistance.

In the United States, a vast quantity of antibiotics is routinely included as low doses in the diet of healthy farm animals, as this practice has been proved to make animals grow faster. Opponents of this practice, however, point out the likelihood that it also leads to antibiotic resistance, frequently in bacteria that are known to also infect humans, although there has been little or no evidence as yet of such transfer of antibiotic resistance actually occurring.

Antibiotic resistance

One side effect of misusing antibiotics is the development of antibiotic resistance by the infecting organisms, similar to the development of pesticide resistance in insects. Evolutionary theory of genetic selection requires that as close as possible to 100% of the infecting organisms be killed off to avoid selection of resistance; if a small subset of the population survives the treatment and is allowed to multiply, the average susceptibility of this new population to the compound will be much less than that of the original population, since they have descended from those few organisms which survived the original treatment. This survival often results from an inheritable resistance to the compound, which was infrequent in the original population but is now much more frequent in the descendants thus selected entirely from those originally infrequent resistant organisms.

Antibiotic resistance has become a serious problem in both the developed and underdeveloped nations. By 1984 half the people with active tuberculosis in the United States had a strain that resisted at least one antibiotic. In certain settings, such as hospitals and some child-care locations, the rate of antibiotic resistance is so high that the normal, low cost antibiotics are virtually useless for treatment of frequently seen infections. This leads to more frequent use of newer and more expensive compounds, which in turn leads inexorably to the rise of resistance to those drugs, and a never-ending ever-spiraling race to discover new and different antibiotics ensues, just to keep us from losing ground in the battle against infection. The fear is that we will eventually fail to keep up in this race, and the time when people did not fear life-threatening bacterial infections will be just a memory of a golden era.

Another example of selection is Staphylococcus aureus, which could be treated successfully with penicillin in the 1940s and 1950s. At present, nearly all strains are resistant to penicillin, and many are resistant to nafcillin, leaving only a narrow selection of drugs such as vancomycin useful for treatment. The situation is worsened by the fact that genes coding for antibiotic resistance can be transferred between bacteria, making it possible for bacteria never exposed to an antibiotic to acquire resistance from those which have. The problem of antibiotic resistance is worsened when antibiotics are used to treat disorders in which they have no efficacy, such as the common cold or other viral complaints, and when they are used widely as prophylaxis rather than treatment (as in, for example, animal feeds), because this exposes more bacteria to selection for resistance.

Antibiotic resistance is the ability of a microorganism to withstand the effects of an antibiotic. Antibiotic resistance develops through mutation or plasmid exchange between bacteria of the same species. If a bacterium carries several resistance genes, it is called multiresistant or, informally, a superbug.

Causes Antibiotic resistance is a consequence of evolution via natural selection. The antibiotic action is an environmental pressure; those bacteria which have a mutation allowing them to survive will live on to reproduce. They will then pass this trait to their offspring, which will be a fully resistant generation.

Several studies have demonstrated that patterns of antibiotic usage greatly affect the number of resistant organisms which develop. Overuse of broad-spectrum antibiotics, such as second and third generation cephalosporins, greatly hastens the development of methicillin resistance, even in organisms that have never been exposed to the selective pressure of methicillin per se. Other factors contributing towards resistance include incorrect diagnosis, unnecessary prescriptions, improper use of antibiotics by patients, and the use of antibiotics as livestock food additives for growth promotion.

Resistant pathogens Staphylococcus aureus (colloquially known as "Staph aureus") is one of the major resistant pathogens. Found on the mucous membranes and the skin of around a third of the population, it is extremely adaptable to antibiotic pressure. It was the first bacterium in which penicillin resistance was found -- in 1947, just four years after the drug started being mass-produced. Methicillin was then the antibiotic of choice. MRSA (methicillin-resistant Staphylococcus aureus) was first detected in Britain in 1961 and is now "quite common" in hospitals. MRSA was responsible for 37% of fatal cases of blood poisoning in the UK in 1999, up from 4% in 1991. Half of all S. aureus infections in the US are resistant to penicillin, methicillin, tetracycline and erythromycin.

This left vancomycin as the only effective agent available at the time. A new class of antibiotics, oxazolidinones, became available in the 1990s, and the first commercially available oxazolidinone, linezolid, is comparable to vancomycin in effectiveness against MRSA. However, VRSA (Vancomycin-resistant Staphylococcus aureus) was first identified in Japan in 1997 and has since been found in hospitals in England, France and the US.

VRSA is also termed GISA (glycopeptide intermediate Staphylococcus aureus) or VISA (vancomycin intermediate Staphylococcus aureus), indicating resistance to all glycopeptide antibiotics.

Enterococcus faecium is another superbug found in hospitals: penicillin resistance was seen in 1983, vancomycin resistance (VRE) in 1987 and linezolid resistance (LRE) in the late 1990s.

Penicillin-resistant pneumonia (or pneumococcus, caused by Streptococcus pneumoniae) was first detected in 1967, as was penicillin-resistant gonorrhea. Resistance to penicillin substitutes is also known beyond S. aureus. By 1993 Escherichia coli was resistant to five fluoroquinolone variants. Mycobacterium tuberculosis is commonly resistant to isoniazid and rifampin and sometimes universally resistant to the common treatments. Other pathogens showing some resistance include Salmonella, Campylobacter, and Streptococci.

Alternatives to antibiotics Prevention Wash hands properly to reduce the chance of getting sick and spreading infection. Wash fruits and vegetables thoroughly. Avoid raw eggs and undercooked meat, especially in ground form. Do not demand antibiotics from your physician. When given antibiotics, take them exactly as prescribed and complete the full course of treatment; do not hoard pills for later use or share leftover antibiotics.

Vaccines Vaccines do not suffer the problem of resistance. This is because a vaccine enhances the body's natural defenses, while an antibiotic operates separately from the body's normal defenses. Nevertheless, new strains may evolve that escape immunity induced by vaccines.

While theoretically promising, anti-staphylococcal vaccines have shown limited efficacy, because of immunological variation between Staphylococcus species, and the limited duration of effectiveness of the antibodies produced. Development and testing of more effective vaccines is under way.

Phage therapy Phage therapy is a more recent alternative that can cope with the problem of resistance.

Beyond antibiotics

Unfortunately, the comparative ease of finding compounds which safely cured bacterial infections proved much harder to duplicate with respect to fungal and viral infections. Antibiotic research led to great strides in our knowledge of basic biochemistry and to the current biological revolution; but in the process it was discovered that the susceptibility of bacteria to many compounds which are safe to humans is based upon significant differences between the cellular and molecular physiology of the bacterial cell and that of the mammalian cell. In contrast, despite the seemingly huge differences between fungi and humans, the basic biochemistries of the fungal cell and the mammalian cell are much more similar; so much so that there are few therapeutic opportunities for compounds to attack a fungal cell which will not harm a human cell. Similarly, we know now that viruses represent an incredibly minimal intracellular parasite, being stripped down to a few genes worth of DNA or RNA and the minimal molecular equipment needed to enter a cell and actually take over the machinery of the cell to produce new viruses. Thus, the great bulk of viral metabolic biochemistry is not merely similar to human biochemistry, it actually is human biochemistry, and the possible targets of antiviral compounds are restricted to the relatively very few components of the actual virus itself.

Aminoglycosides are a group of antibiotics that are effective against certain types of bacteria. They include amikacin, gentamicin, kanamycin, neomycin, netilmicin, paromomycin, streptomycin, and tobramycin. Those which are derived from Streptomyces species are named with the suffix -mycin, while those which are derived from micromonospora are named with the suffix -micin.

Aminoglycosides work by binding to the bacterial 30S ribosomal subunit, causing misreading of t-RNA, leaving the bacterium unable to synthesize proteins vital to its growth.

Aminoglycosides are useful primarily in infections involving aerobic, Gram-negative bacteria, such as Pseudomonas, Acinetobacter, and Enterobacter. In addition, some mycobacteria, including the bacteria that cause tuberculosis, are susceptible to aminoglycosides. Streptomycin was the first effective drug in the treatment of tuberculosis, though the role of aminoglycosides such as streptomycin and amikacin have been eclipsed (because of their toxicity and inconvenient route of administration) except for multiple drug resistant strains.

Infections caused by Gram-positive bacteria can also be treated with aminoglycosides, but other types of antibiotics are more potent and less damaging to the host. In the past the aminoglycosides have been used in conjunction with penicillin-related antibiotics in streptococcal infections for their synergistic effects, particularly in endocarditis.

Because of their potential for ototoxicity and renal toxicity, aminoglycosides are administered in doses based on body weight. Blood drug levels and creatinine are monitored during the course of therapy.

There is no oral form of these antibiotics: they are generally administered intravenously, though some are used in topical preparations used on wounds.

Aminoglycosides are completely ineffective against anaerobic bacteria, fungi and viruses.

Gentamicin is a aminoglycoside antibiotic, and can treat many different types of bacterial infections, particularly Gram-negative infection.

Gentamicin works by binding to a site on the bacterial ribosome, causing the genetic code to be misread.

Like all aminoglycosides, gentamicin does not pass the gastro-intestinal tract, so it can only be given intravenously or intramuscularly.

Gentamicin can cause deafness or a loss of equilibrioception in genetically susceptible individuals. These individuals have a normally harmless mutation in their DNA, that allows the gentamicin to affect their cells. The cells of the ear are particularly sensitive to this.

Gentamicin can also be highly nephrotoxic, particularly if multiple doses accumulate over a course of treatment. For his reason gentamicin is usually dosed by body weight. Various formulae exist for calculating gentamicin dosage. Also serum levels of gentamicin are monitored during treatment.

Neomycin is an antibiotic that is found in many topical medications such as creams, ointments and eyedrops.

It can also be given orally, where it is usually combined with other antibiotics. Oral use is extremely rare because neomycin is extremely nephrotoxic, especially compared to other aminoglycosides.

Neomycin was discovered in 1949 by the microbiologist Selman Waksman. It is produced naturally by the bacterium Streptomyces fradiae.

Neomycin has a broad spectrum of effect, killing both gram-positive and gram negative bacteria. It is relatively toxic to humans, and some people have allergic reactions to it.

Neomycin is used in the lab in agar plates when culturing organisims anaerobically. Neomycin stops the growth of gram-negative bacilli and staphylcocci, allowing Streptococcus species to grow more abundantly.

Streptomycin was the first of a class of drugs called aminoglycosides to be discovered, and was the first antibiotic remedy for tuberculosis. It is derived from the actinobacterium Streptomyces griseus.

It was first isolated on October 19, 1943 by Albert Schatz, a research student at Rutgers University, New Jersey, USA. However, according to academic tradition, Schatz's supervisor, Professor Selman Abraham Waksman, took credit for his student's discovery and received the Nobel prize in Physiology in 1952. Schatz was belatedly awarded the Rutgers medal in 1994, at the age of 74.

Streptomycin cannot be given orally, but must be administered by regular intramuscular injection.

Ertapenem is an carbapenem antibiotic marketed under the name INVANZ.

It is similar to the earlier imipenem, but has a longer half-life. The marketing slogan is The Power of One, as the dose is one gram, once a day. It must be given parenterally (by injection or infusion).

It is designed to be more effective against gram-negative bacteria than its predecessor. It is not effective against MRSA or Pseudomonas aeruginosa.

Meropenem is an ultra-broad spectrum injectable antibiotic for a wide variety of serious infections, including meningitis and pneumonia.

Meropenem was developed by Sumitomo Pharmaceuticals. It is marketed outside Japan by AstraZeneca with the brand names Merrem and Meronem.

The cephalosporins, are a class of ß-lactam antibiotics. Together with cephamycins they belong to a sub-group called cephems.

History Cephalosporin was first isolated from cultures of Cephalosporium acremonium from a sewer in Sardinia in 1948 by an italian scientist Giuseppe Brotzu. He noticed that these cultures produced a substance that was effective against salmonella typhi, the cause of typhoid. In 1960s, Eli Lilly launched the first cephalosporins on the market.

Mode of action Cephalosporins work the same way as penicillins, they interfere with the peptidoglycan synthesis of the bacterial wall by inhibiting the final transpeptidation needed for the cross-links. This effect is bactericidal.

Cephalosporin nucleusThe generations The cephalosporin nucleus can be modified to gain different properties.

First generation cephalosporins First generation cephalosporins have a spectrum of activity that includes penicillinase-producing, methicillin-susceptible staphylococci and streptococci, though they are not the drugs of choice for such infections. They also have activity against some Escherichia coli, Klebsiella pneumoniae and Proteus mirabilis, but have no activity against Bacteroides fragilis, enterococci, methicilllin-resistant staphylococci, Pseudomonas, Acinetobacter, Enterobacter, indole-positive Proteus or Serratia.

cephazolin (cefazolin) cephalothin cephapirin cephalexin cephradine cephadroxil cephaclor Second generation cephalosporins The second generation cephalosporins have a greater gram-negative spectrum while retaining some activity against gram-positive cocci. They are also more resistant to beta-lactamase.

cefamandole cefuroxime cefonicid ceforanid cefaclor cefixime cefprozil cefpodoxime loracarbef cefotetan Third generation cephalosporins Third generation cephalsporins have a broad spectrum of activity against enteric gram-negative rods and thus are particularly useful in treating hospital-acquired infections.

ceftriaxone cefotaxime ceftizoxime ceftazidime cefoperazone cefepime cefpirome cefsulodin ceftibuten cefixime cefatamet

Cephamycins are a group of beta-lactam antibiotics, very similar to cephalosporins. Together with cephalosporins the form a sub-group of antibiotics called cephems. Cephamycins are originally produced by Streptomyces, but synthetic ones have been produced as well.

Beta-lactam in a heteroatomic ring structure, consisting of three carbon atoms and one nitrogen atom (Fig. 1). The beta-lactam ring is part of several antibiotics, such as penicillin, which are therefore also called beta-lactam antibiotics. These antibiotics work by inhibiting the bacterial cell wall synthesis. This has a lethal effect on bacteria, especially on Gram-positive ones. Bacteria can become resistant against beta-lactam antibiotics by expressing beta-lactamase.

Cephalexin is a drug that is a member of the cephalosporin class of antibiotics. It is one of the most widely prescribed antibiotics, often used for the treatment of superficial infections that result as complications of minor wounds or lacerations.

It is sold generically or under the brand name Keflex.

Cefuroxime has been widely available in the USA since 1977. It is also available under the brand name Ceftin.

Classification Cefuroxime is a β-lactam type Antibiotic. More specifically, it is a second-generation cephalosporin. Its Anatomical Therapeutic Chemical Classification System code is J01DA06.

Patient Information Like most antibiotics, it can have severe effects on the digestive system, but taking Cefuroxime with meals can minimize its side effects. Do NOT take antacids; they may reduce the drug's effect. Acidophilus supplements should be used, as directed, instead of antacids. Tell your doctor if you have medical problems associated with your digestive system or kidneys. Also, like most antibiotics, it is important to finish the prescription, to avoid antibiotic resistance. Cefuroxime is used to treat many different types of bacterial infections such as bronchitis, sinusitis, tonsillitis, ear infections, skin infections, gonorrhea, and urinary tract infections.

Penicillin is a β-lactam antibiotic used in the treatment of bacterial infections caused by susceptible, usually Gram-positive, organisms. The name "penicillin" can either refer to several variants of penicillin available, or to the group of antibiotics derived from the penicillins.

Penicillin has a molecular formula R-C9H11N2O4S, where R is a variable side chain.

Penicillin was originally isolated from the Penicillium chrysogenum (formerly Penicillium notatum) mould. The antibiotic effect was originally discovered by a young French medical student Ernest Duchesne studying Penicillium glaucum in 1896 but his work had no lasting consequences.

It was later rediscovered in 1928 by Alexander Fleming who noticed a halo of inhibition of bacterial growth in a culture of Staphylococcus around a contaminant blue-green mould. From the culture plate, Fleming concluded that the mould was releasing a substance that was inhibiting bacterial growth. He grew a pure culture and discovered that the fungus was Penicillium notatum - he later named the bacterial inhibiting substance penicillin after the Penicillium notatum that released it. Fleming was convinced after conducting some more experiments that penicillin could not last long enough in the human body to kill pathogenic bacteria and stopped studying penicillin after 1931. It would prove to be the discovery that changed modern medicine. In 1939, Howard Walter Florey and a team of researchers at Oxford University made significant progress in showing Penicillin's in vivo ability to kill infectious bacteria. This eventually led to commercial production of penicillin.

During World War II, penicillin made a major difference in the number of deaths and amputations caused by infected wounds amongst Allied forces. Availability was severely limited, however, by the difficulty of manufacturing large quantities of penicillin and by the rapid renal clearance of the drug necessitating frequent dosing. Penicillins are actively secreted and about 80% of a penicillin dose is cleared within three to four hours of administration. During those times it became common procedure to collect the urine from patients being treated so that the penicillin could be isolated and reused. (Silverthorn, 2004)

This was not a satisfactory solution, however, so researchers looked for a way to slow penicillin secretion. They hoped to find a molecule that could compete with penicillin for the organic acid transporter responsible for secretion such that the transporter would preferentially secrete the competitive inhibitor. The uricosuric agent probenecid proved to be suitable. When probenecid and penicillin are concomitantly administered, probenecid competitively inhibits the secretion of penicillin, increasing its concentration and prolonging its activity. The advent of mass-production techniques and semi-synthetic penicillins solved supply issues, and this use of probenecid declined. (Silverthorn, 2004) Probenecid is still clinically useful, however, for certain infections requiring particularly high concentrations of penicillins. (Rossi, 2004)

The chemical structure of penicillin was determined by Dorothy Crowfoot Hodgkin, enabling synthetic production. A team of Oxford research scientists led by Australian Howard Walter Florey and including Ernst Boris Chain and Norman Heatley discovered a method of mass producing the drug. Florey and Chain shared the 1945 Nobel prize in medicine with Fleming for this work. Penicillin has since become the most widely used antibiotic to date and is still used for many Gram-positive bacterial infections.

Mode of action Main article: beta-lactam antibiotic

Penicillin and other ß-lactam antibiotics work by inhibiting the formation of peptidoglycan cross links in the bacterial cell wall. The beta-lactam moiety of penicillin binds to the enzyme that links the peptidoglycan molecules in bacteria and prevents the bacteria from multiplying (or rather causing cell lysis or death when the bacteria tries to divide).

Variants Benzathine penicillin Benzathine penicillin is slowly absorbed into the circulation, after intramuscular injection, and hydrolysed to benzylpenicillin in vivo. It is the drug-of-choice when prolonged low concentrations of benzylpenicillin are required and appropriate, allowing prolonged antibiotic action over 2-4 weeks after a single IM dose. It is marketed by Wyeth under the trade name Bicillin®.

Specific indications for benzathine pencillin include: (Rossi, 2004)

prophylaxis of rheumatic fever early or latent syphilis Benzylpenicillin (penicillin G)

Penicillin G (Benzylpenicillin)Benzylpenicillin, commonly known as penicillin G, is the gold standard penicillin - higher tissue concentration of can be achieved than is possible with phenoxymethylpenicillin. These higher concentrations translate to increased antibacterial activity.

Specific indications for benzylpenicillin include: (Rossi, 2004)

bacterial endocarditis meningitis aspiration pneumonia, lung abscess community-acquired pneumonia syphilis septicaemia in children Phenoxymethylpenicillin (penicillin V) Phenoxymethylpenicillin, commonly known as penicillin V, is the orally-active form of penicillin. It is less active than benzylpenicillin, however, and is only appropriate in conditions where high tissue concentrations are not required.

Specific indications for phenoxymethylpenicillin include: (Rossi, 2004)

infections caused by Streptococcus pyogenes tonsilitis pharyngitis skin infections prophylaxis of rheumatic fever moderate-to-severe gingivitis (with metronidazole) Procaine penicillin Procaine penicillin is a combination of benzylpenicillin with the local anaesthetic agent procaine. This combination is aimed at reducing the pain and discomfort associated with a large intramuscular injection of penicillin.

Specific indications for procaine penicillin include: (Rossi, 2004)

respiratory tract infections where compliance with oral treatment is unlikely syphilis cellulitis Resistance Antibiotic resistance to penicillin is now common amongst many hospital acquired bacteria. The resistance to penicillin has been partly (maybe mostly) due to the rise of beta-lactamase producing bacteria which secrete an enzyme that breaks down the beta-lactam ring of penicillin, rendering it harmless to the bacteria.

Developments from penicillin The narrow spectrum of activity of the penicillins, along with the poor activity of the orally-active phenoxymethylpenicillin, led to the search for derivatives of penicillin which could treat a wider range of infections.

The first real step forward was in the form of ampicillin. Ampicillin offered a broader spectrum of activity than either of the original penicillins and allowed doctors to treat a broader range of both Gram-positive and Gram-negative infections. Further developments led to amoxicillin, with improved duration-of-action.

Further development gave us flucloxacillin, important even now for its resistance to beta-lactamases produced by bacteria such as Staphylococcus species. It is still no match for MRSA (Methicillin Resistant Staphylococcus aureus).

The last in the line of true penicillins were the antipseudomonal penicillins, such as ticarcillin, useful for their activity against Gram-negative bacteria. However, the usefulness of the beta-lactam ring was such that related antibiotics, including the mecillinams, the carbapenems and, most importantly, the cephalosporins, have it at the centre of their structures.

Biosynthesis

Penicillin biosynthesisThe precursor compound ACV-tripeptide (δ-(L-α-amino-adipate)-L-cysteine-D-valine) is biosynthesized in bacteria and fungi from the monomeric L-amino acids by the enzyme ACV-synthetase (EC 6.3.2.26), a nonribosomal peptide synthetase. The ACV-tripeptide is cyclized by isopenicillin-N-synthetase (EC 1.21.3.1) to isopenicillin N, thereby forming the beta-lactam nucleus. The isopenicillin N N-acyltransferase (EC 2.3.1.164) exchanges the sidechain, yielding a broad range of different penicillins depending on the utilized CoA-bound carboxylic acids. The synthesis of the cephalosporin-type antibiotics starts with isopenicillin N. (Moss, 2002)

Vancomycin is an antibiotic used in the prophylaxis and treament of infections caused by Gram-positive bacteria. It is a branched tricyclic glycosylated nonribosomal peptide produced by the fermentation of the actinomycete bacteria Amycolatopsis orientalis (formerly Nocardia orientalis).

It is often reserved as the "drug of last resort", used only after treatment with other antibiotics had failed. With the increasing prevalence of antibiotic resistant-bacteria, vancomycin has increasingly become a first line therapy when faced with Staphylococcus aureus infections in a patient where antibiotic resistance can reasonably be anticipated.

Vancomycin hydrochloride has been developed and marketed by Eli Lilly under the trade name Vancocin®. Their patent expired in the early 1980s and generic versions of the drug are now available internationally under various trade names.

Vancomycin acts by inhibiting proper cell wall synthesis in Gram-positive bacteria. The mechanism inhibited, and various factors related to entering the outer membrane of Gram-negative organisms mean that vancomycin is not active against Gram-negative bacteria.

Specifically, vancomycin prevents incorporation of N-acetylmuramic acid (NAM)- and N-acetylglucosamine (NAG)-peptide subunits from being incorporated into the peptidoglycan matrix; which forms the major structural component of Gram-positive cell walls.

The large hydrophilic molecule is able to form hydrogen bond interactions with the terminal D-alanyl-D-alanine moieties of the NAM/NAG-peptides. Normally this is a five-point interaction. This binding of vancomycin to the D-Ala-D-Ala prevents the incorporation of the NAM/NAG-peptide subunits into the peptidoglycan matrix.

Therapeutic considerations Owing to its renal excretion and nephrotoxic potential, vancomycin must be used cautiously in patients with poor renal function, or when given in conjunction with other nephrotoxic drugs. This dose and/or dosing interval are reduced in patients with renal impairment. Vancomycin may also potentially cause ototoxicity. These risk of nephrotoxic and ototoxic effects are increased with concomitant administration of aminoglycoside antibiotics.

Antibiotic (Greek anti, “against”; bios, “life”), any chemical compound used to kill or inhibit the growth of infectious organisms, particularly bacteria and fungi. All antibiotics share the property of selective toxicity: they are more toxic to an invading organism than they are to an animal or human host. Penicillin is the most well-known antibiotic and has been used to fight many infectious diseases, including syphilis, gonorrhoea, tetanus, and scarlet fever. Another antibiotic, streptomycin, is used to combat tuberculosis (TB). Originally the term antibiotic referred only to organic compounds, produced by bacteria or moulds, that are toxic to other micro-organisms.

The term now includes synthetic and semi-synthetic as well as organic compounds. Antibiotic refers primarily to antibacterials but also includes anti-malarials and anti-protozoals. There are also a number of antivirals, but most viral infections cannot and should not be treated with an antibiotic. Although the antibiotic mechanism was not scientifically understood until the 20th century, the principal of using organic compounds to fight infection has been known since ancient times. Crude plant extracts were used medicinally for centuries, and there is anecdotal evidence for the use of cheese moulds for topical treatment of infection.

The first observation of what would now be called an antibiotic effect was made in the 19th century by the French chemist Louis Pasteur, who discovered that certain saprophytic bacteria can kill anthrax germs. In about 1900, German bacteriologist Rudolf von Emmerich isolated a substance called pyocyanase, which can kill the germs of cholera and diphtheria in a test tube. It did not prove useful, however, in curing disease.

In the first decade of the 20th century, the German doctor and chemist Paul Ehrlich began experimenting with the synthesis of organic compounds that would selectively attack an infecting organism without harming the host organism. His experiments led to the development, in 1909, of salvarsan, a synthetic compound containing arsenic, which exhibited selective action against spirochaetes, the bacteria that cause syphilis. Salvarsan remained the only effective treatment for syphilis until the purification of penicillin in the 1940s. In the 1920s British bacteriologist Alexander Fleming, who later discovered penicillin, found a substance called lysozyme in many bodily secretions, such as tears and sweat, and in certain other plant and animal substances. Lysozyme has strong antimicrobial activity, but mainly against harmless bacteria. i, i. Penicillin, the archetype of antibiotics, is a derivative of the mould Penicillium notatum. Penicillin was discovered accidentally in 1928 by Fleming, who showed its effectiveness in laboratory cultures against many disease-producing bacteria, such as those that cause gonorrhoea and certain types of meningitis and septicaemia. This discovery marked the beginning of the development of antibacterial compounds produced by living organisms. Penicillin was first used on human beings by Howard Florey and Ernst Chain in 1940.

It is unnecessary to monitor serum concentrations of vancomycin in most patients. However there are circumstances which warrant therapeutic drug monitoring (TDM) such as patients receiving concomitant aminoglycoside therapy, patients with (potentially) altered pharmacokinetic parameters, patients on haemodialysis, during high dose or prolonged treatment, and patients with impaired renal function. (Rossi, 2004)

Vancomycin needs to be given intravenously (IV) for systemic therapy since it does not cross through the intestinal lining. It is a large hydrophilic molecule which partitions poorly across the gastrointestinal mucosa. Vancomycin must be administered in a dilute solution slowly, over at least 60 minutes, due to the high incidence of pain and thrombophlebitis.

The only indication for oral vancomycin therapy is in the treatment of pseudomembranous colitis, where it must be given orally to get to reach the site of infection in the colon.

Clinical indications Vancomycin is indicated for the treatment of serious, life-threatening infections by Gram-positive bacteria which is unresponsive to other less toxic antibiotics.

The increasing emergence of vancomycin-resistant enterococci has resulted in the develop of guidelines for use by the Centers for Disease Control (CDC) Hospital Infection Control Practices Advisory Committee. These guidelines restrict use of vancomycin to the following indications:

treatment of serious infections caused by susceptible organisms resistant to penicillins (MRSA and multi-resistant Staphylococcus epidermidis (MRSE)) or in people with serious allergy to penicillins pseudomembranous colitis (relapse or unresponsive to metronidazole treatment) antibacterial prophylaxis for endocarditis following certain procedures in penicillin-hypersensitive people at high risk surgical prophylaxis for major procedures involving implantation of prostheses in institutions with a high rate of MRSA or MRSE (Rossi, 2004)

Resistance As of July 2002, there were reports of a woman in the city of Detroit, United States, having been infected by a strain of Staphylococcus aureus resistant to vancomycin. She was kept in isolation to prevent the infection from being spread to others.

Resistance to vancomycin, such as in the above case, appears to be a growing problem for healthcare sector. With vancomycin being the last-line antibiotic for serious Gram-positive infections there is a fear that resistance to even this will result in a return to the days when fatal bacterial infections were common.

There is some suspicion that agricultural use of avoparcin, another similar glycopeptide antibiotic, has contributed to the emergence of vancomycin-resistant organisms.

The mechanism of resistance appears to be alteration to the terminal amino acid residues of the NAM/NAG-peptide subunits, normally D-alanyl-D-alanine, which vancomycin binds to. Variations such as D-alanyl-D-lactate and D-alanyl-D-serine result in only a 4-point hydrogen bonding interaction being possible between vancomycin and the peptide. This loss of just one point of interaction results in a 1000-fold decrease in affinity.

In Enterococci this modification appears to be due to the expression of an enzyme which alters the terminal residue. Three main resistance variants have been characterised to date among resistant Enterococcus faecium and E. faecalis populations.

VanA - resistance to vancomycin and teicoplanin, inducible on exposure to these agents VanB - lower level resistance, inducible by vancomycin but strains may remain susceptible to teicoplanin VanC - least clinically important, resistance only to vancomycin, constitutive resistance The development of novel antibiotics such as linezolid is expected to delay, but not halt, the emergence of bacteria resistant to all available antibiotics.

Teicoplanin is an antibiotic used in the prophylaxis and treatment of serious infections caused by Gram-positive bacteria. Like vancomycin, it is a glycopeptide antiobiotic with a similar spectrum of activity. Teicoplanin is marketed by Aventis under the trade name Targocid®.

The first antibiotic to be used in the treatment of human disease was tyrothricin, isolated from certain soil bacteria by the American bacteriologist René Dubos in 1939. This substance is too toxic for general use, but it is employed in the external treatment of certain infections. Other antibiotics produced by a group of soil bacteria called actinomycetes have proved more successful. One of these, streptomycin, discovered in 1944 by the American biologist Selman Waksman and his associates, is effective against many diseases—including several against which penicillin is useless, especially tuberculosis. Since antibiotics came into general use in the 1950s, they have transformed the patterns of disease and death. Many diseases that once headed the mortality tables—such as TB, pneumonia, and septicaemia—now hold lower positions, although TB has re-emerged in parts of the developed world.

Surgical procedures, too, have been improved enormously, because lengthy and complex operations can now be carried out without a prohibitively high risk of infection. Chemotherapy has also been used in the treatment or prevention of protozoal and fungal diseases, especially malaria, a major killer in developing nations. Slow progress is being made in the chemotherapeutic treatment of viral diseases. Drugs have been developed and used to treat shingles and chickenpox. There is also a continuing effort to find a cure for infection by the human immunodeficiency virus (HIV), which now occurs worldwide. There is, however, the growing problem of resistance to antibiotics, so that new ones are constantly being researched.

Antibiotics can either selectively disrupt the cell membrane in some species of bacteria and fungi, or block bacterial protein synthesis. The antifungal amphotericin, for example, disrupts the chemical structure of the cell membrane in fungi, thereby preventing vital nutrients from being absorbed and allowing toxins into the fungal cell. Most antibiotics operate by inhibiting the synthesis of various cell components. Some important and clinically useful drugs interfere with the synthesis of peptidoglycan, the most important component of the cell wall. These drugs include the β-lactam antibiotics, which are classified according to chemical structure into penicillins, cephalosporins, and carbapenems. All of the β-lactam antibiotics contain a ring as part of their chemical structure. l, e, h. The ring is critical in preventing peptides from attaching to side chains during cell-wall formation. These compounds all inhibit peptidoglycan synthesis but do not interfere with the synthesis of the intracellular components. The continuing build-up of materials inside the cell exerts ever greater pressure on the membrane, which is no longer properly supported by peptidoglycan. The membrane gives way, the cell contents leak out, and the bacterium dies. These antibiotics are safe for use in humans because human cells do not have cell walls.

The macrolides are a group of drugs (typically antibiotics) whose activity stems from the presence of a macrolide ring, a large lactone ring to which one or more deoxy sugars, usually cladinose and desosamine, are attached. The lactone ring can be either 14, 15 or 16-membered. Macrolides belong to the polyketide class of natural products.

The most commonly-prescribed macrolide antibiotics are:

erythromycin clarithromycin azithromycin roxithromycin Others are: spiramycin (used for treating toxoplasmosis), ansamycin, oleandomycin, carbomycin and tylocine.

There is also a new class of antibiotics called ketolides that is structurally related to the macrolides. Ketolides such as telithromycin are used to fight respiratory tract infections caused by macrolide-resistant bacteria.

Non-antibiotic macrolides The drug Tacrolimus, which is used as an immunosuppresant, is also a macrolide. It has similar activity to cyclosporine. While it does have antibiotic properties, it is not approved for antibiotic usage due to its strong effects on the immune system.

Uses Macrolides are used to treat infections such as respiratory tract infections and soft tissue infections. The antimicrobial spectrum of macrolides is slightly wider than that of penicillin. Beta-hemolytic streptococci, pneumococci, staphylococci and enterococci are usually susceptible to macrolides. Unlike penicillin, macrolides have shown effective against mycoplasma, mycobacteria, some rickettsia and chlamydia.

Mechanism of action The mechanism of action of the macrolides is inhibition of bacterial protein synthesis by binding reversibly to the subunit 50S of the bacterial ribosome, thereby inhibiting translocation of peptidyl-tRNA. This action is mainly bacteriostatic, but can also be bactericidal in high concentrations. Macrolides tend to accumulate within leucocytes, and are therefore actually transported into the site of infection.

Resistance Bacterial resistance to macrolides occurs by alteration of the structure of the bacterial ribosome. This resistance can be either plasmid-mediated or chromosomal, i.e through mutation.

Erythromycin is a macrolide antibiotic which has an antimicrobial spectrum similar or slightly wider to that of penicillin, and is often used for people who have an allergy to penicillins. For respiratory tract infections, it has better coverage of atypical organisms, including mycoplasma. It is also used to treat outbreaks of chlamydia, syphilis, and gonorrhea.

Erythromycin is produced from a strain of the actinomyces Saccaropolyspora erythraea, formerly known as Streptomyces erythraeus.

Abelardo Aguilar, a Filipino scientist sent some soil samples to his employer Eli Lilly in 1949. Eli Lilly’s research team, led by J. M. McGuire, managed to isolate erythromycin, and it was subsequently launched in 1952 under the brand name Ilosone (after the Philippine region of Iloilo where it was originally collected from). Erythromycin was formerly also called ilotycin.

Available forms Erythromycin is available in enteric-coated tablets, oral suspensions, ointments, gels and injections.

Mechanism of action Erythromycin prevents bacteria from growing, by interfering with their protein synthesis. Erythromycin binds to the subunit 50S of the bacterial ribosome, and thus inhibits the translocation of peptides.

Many antibiotics operate by inhibiting the synthesis of various intracellular bacterial molecules, including DNA, RNA, ribosomes, and proteins. The synthetic sulphonamides are among the antibiotics that interfere with protein synthesis. Nucleic-acid synthesis can be stopped by antibiotics which inhibit the enzymes that assemble the polymers—for example, DNA polymerase or RNA polymerase. Examples of such antibiotics are actinomycin and rifampicin, the last one being particularly valuable in the treatment of TB. The quinolone antibiotics inhibit synthesis of an enzyme responsible for the coiling and uncoiling of the chromosome, a process necessary for DNA replication and for transcription to messenger RNA.

Some antibacterials affect messenger RNA by causing its genetic message to be garbled. When these faulty messages are translated, the protein products are non-functional. There are also other mechanisms: the tetracyclines compete with incoming transfer-RNA molecules; the aminoglycosides cause the genetic message to be misread and a defective protein to be produced; and chloramphenicol prevents the linking of amino acids to the growing protein. In some species of bacteria the cell wall consists primarily of a thick layer of peptidoglycan.

Other species have a much thinner layer of peptidoglycan and an outer membrane. When bacteria are subjected to a Gram's stain, these differences in structure affect the differential staining of the bacteria with a dye called gentian violet and other solutions. The differences in staining coloration (gram-positive bacteria appear purple and gram-negative bacteria appear colourless or reddish, depending on the process used) are the basis of the classification of bacteria into gram-positive (those with thick peptidoglycan) and gram-negative (those with thin peptidoglycan and an outer membrane), because the staining properties correlate with many other bacterial properties. Antibacterials can be further subdivided into narrow-spectrum and broad-spectrum agents. a, k, l, c, g. The narrow-spectrum penicillins fight many gram-positive bacteria. Aminoglycosides, also narrow-spectrum, work against gram-negative bacteria. The tetracyclines and chloramphenicols are both broad-spectrum drugs, effective against both gram-positive and gram-negative bacteria.

Pharmacokinetics Erythromycin is easily inactivated by gastric acids, therefore all orally administered formulations are given as either enteric coated or as more stable salts or esters. Erythromycin is very rapidly absorbed, and diffused into most tissues and phagocytes. Due to the high concentration in phagocytes, erythromycin is actively transported to the site of infection, where during active phagocytosis, large concentrations of erythromycin are released.

Metabolism Most of erythromycin is metabolised by demethylation in the liver. Its main route elimination route is in the bile, and a small portion in the urine. Erythromycin's half-life is 1.5 hours.

Side-effects Gastrointestinal intestinal disturbances such as diarrhoea, nausea, abdominal pain and vomiting are fairly common so it tends not to be prescribed as a first-line drug. More serious side-effects, such as reversible deafness are rare. Earlier case reports on sudden death prompted a study on a large cohort that confirmed a link between erythromycin, ventricular tachycardia and sudden cardiac death in patients also taking drugs that prolong the metabolism of erythromycin (like verapamil or diltiazem) by interfering with CYP3A4 (Ray et al 2004).

Azithromycin is the first macrolide antibiotic belonging to the azalide group. Azithromycin is derived from erythromycin by adding a nitrogen atom into the lactone ring of erythromycin A, thus making lactone ring 15-membered. Azithromycin is sold under the brand name of Zithromax and Sumamed, and is one of the world's best selling antibiotics. Azithromycin is used for the treatment of respiratory tract, soft-tissue and genitourinary infections.

Azithromycin's name is derived from the azane-substituent and erythromycin. Its accurate chemical name is 2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-[ (2,6-dideoxy-3-C-methyl-3-O -methyl-a-L-ribo-hexopyranosyl)oxy]-2-ethyl-3,4,10- trihydroxy-3,5,6,8,10,12,14-heptamethyl-11- [[3,4,6-trideoxy-3-(dimethylamino)-b-D- xylo-hexopyranosyl]oxy]-1-oxa-6- azacyclopentadecan-15-one.

History A team of Pliva's researchers, Gabrijela Kobrehel, Gorjana Radobolja-Lazarevski and Zrinka Tamburasev led by Dr Slobodan Dokic, discovered azithromycin in 1980. It was patented in 1981, and was later found by Pfizer's scientists while going through patent documents. In 1986 Pliva and Pfizer signed a licensing agreement, which gave Pfizer exclusive rights for the sale of azithromycin in the Western Europe and United States. Pliva brought their azithromycin on the market in Central and Eastern Europe under the brand name of Sumamed in 1988, and Pfizer Zithromax in 1991.

Available forms Azithromycin is commonly administered in tablet or oral suspension. It is also available for intravenous injection.

Mechanism of action Azithromycin prevents bacteria from growing, by interfering with their protein synthesis. Azithromycin binds to the subunit 50S of the bacterial ribosome, and thus inhibits the translocation of peptides. Azithromycin has similar antimicrobial spectrum as erythromycin, but is more effective against certain gram-negative bacteria, particularly Hemophilus influenzae.

Pharmacokinetics Unlike erythromycin, azithromycin is acid-stable and can therefore be taken orally without being protected from gastric acids. It is readily absorbed, and diffused into most tissues and phagocytes. Due to the high concentration in phagocytes, azithromycin is actively transported to the site of infection. During active phagocytosis, large concentrations of azithromycin is released. The concentration of azithromycin in the tissues can be over 50 times higher than in plasma. This is due to ion trapping and the high lipid solubility.

Metabolism Azithromycin's half-life is approximately 2 days, and it's fairly resistant to metabolic inactivation. Its main elimination route is through excretion in to the biliary fluid, and some can also be eliminated through urinary excretion. Azithromycin is excreted through both of these elimination routes mainly in unchanged form.

Side effects Most common side-effects are gastrointestinal; diarrhea, nausea, abdominal pain and vomiting.

Clarithromycin is a macrolide antibiotic used to treat pharyngitis, tonsillitis, acute maxillary sinusitis, acute bacterial exacerbation of chronic bronchitis, pneumonia (especially atypical pneumonias associated with Chlamydia pneumoniae or TWAR), skin and skin structure infections, and, in HIV and AIDS patients to prevent, and to treat, disseminated Mycobacterium avium complex or MAC.

Clarithromycin is available under several brandnames for example Biaxin and Klacid.

Abbott Laboratories brought out clarithromycin in 1991.

Available forms Clarithromycin is commonly administered in tablets, extended-release tablets or oral suspension.

Mechanism of action Clarithromycin prevents bacteria from growing, by interfering with their protein synthesis. Clarithromycin binds to the subunit 50S of the bacterial ribosome, and thus inhibits the translocation of peptides. Clarithromycin has similar antimicrobial spectrum as erythromycin, but is more effective against certain gram-negative bacteria, particularly Legionella pneumophilae. Besides this bacteriostatic effect, clarithromycin also has bactericidal effect on certain strains such as Haemophilus influenzae, Streptococcus pneumoniae and Neisseria gonorrhoeae.

Pharmacokinetics Unlike erythromycin, clarithromycin is acid-stable and can therefore be taken orally without being protected from gastric acids. It is readily absorbed, and diffused into most tissues and phagocytes. Due to the high concentration in phagocytes, clarithromycin is actively transported to the site of infection. During active phagocytosis, large concentrations of clarithromycin is released. The concentration of clarithromycin in the tissues can be over 10 times higher than in plasma. Highest concentrations were found in liver and lung tissue.

Metabolism Clarithromycin has a fairly rapid first-pass hepatic metabolism, i.e it is metabolised by the liver. However, this metabolite, 14-hydroxy clarithromycin is almost twice as active as clarithromycin. The half-life of clarithromycin is about 5 hours and 14-hydroxy clarithromycin's about 7 hours. Clarithromycin's and its metabolites' main routes of elimination are urinary and biliary excretion.

Side effects Most common side-effects are gastrointestinal; diarrhoea, nausea, abdominal pain and vomiting. Less common side-effects include headaches, rashes, alteration in senses of smell and taste.

Roxithromycin is a semi-synthetic macrolide antibiotic. It is used to treat respiratory tract, urinary and soft tissue infections. Roxithromycin is derived from erythromycin, containing the same 14-membered lactone ring. However, an N-oxime side chain is attached to the lactone ring.

Roxithromycin is available under several brandnames, for example Surlid and Rulid

French pharmaceutical company Hoechst Uclaf brought out roxithromycin in 1987.

Available forms Roxithromycin is commonly administered in tablets or oral suspension.

Mechanism of action Roxithromycin prevents bacteria from growing, by interfering with their protein synthesis. Roxithromycin binds to the subunit 50S of the bacterial ribosome, and thus inhibits the translocation of peptides. Roxithromycin has similar antimicrobial spectrum as erythromycin, but is more effective against certain gram-negative bacteria, particularly Legionella pneumophilae.

Pharmacokinetics When taken before a meal, roxithromycin is very rapidly absorbed, and diffused into most tissues and phagocytes. Due to the high concentration in phagocytes, roxithromycin is actively transported to the site of infection. During active phagocytosis, large concentrations of roxithromycin are released.

Metabolism Only a small portion of roxithromycin is metabolised. Most of roxithromycin is secreted unchanged into the bile and some in expired air. Under 10% is excreted into the urine. Roxithromycin's half-life is 12 hours.

Side effects Most common side-effects are gastrointestinal; diarrhoea, nausea, abdominal pain and vomiting. Less common side-effects include headaches, rashes, abnormal liver function values and alteration in senses of smell and taste.

Ketolides are antibiotics belonging to the macrolide group. Ketolides are derived from erythromycin by substituting the cladinose sugar with a keto-group and attaching a cyclic carbamate group in the lactone ring. These modifications give ketolides much broader spectrum than other macrolides. Moreover, ketolides are effective against macrolide-resistant bacteria, due to their ability to bind at two sites at the bacterial ribosome.

The only ketolide on the market at this moment is telithromycin, which is sold under the brand name of Ketek.

Another promising ketolide is cethromycin.

Telithromycin is the first ketolide antibiotic to enter clinical use. It is used to treat serious macrolide-resistant respiratory infections. Telithromycin is sold under the brand name of Ketek.

Telithromycin is a semi-synthetic erythromycin derivative. It is created by substituting the cladinose sugar with a ketogroup and adding a carbamate ring in the lactone ring. An alkyl-aryl moiety is attached to this carbamate ring. Furthermore, the carbon at position 6 has been methylated, like in clarithromycin, to achieve better acid-stability.

French pharmaceutical company Hoechst Marion Roussel (later Aventis) started phase II/III trials of telithromycin (HMR-3647) in 1998. Telithromycin was approved by the European Commission in July 2001 and subsequently came on sale in October 2001. In USA, telithromycin gained FDA approval April 1, 2004 .

Available forms Telithromycin is administered as tablets.

Mechanism of action Telithromycin prevents bacteria from growing, by interfering with their protein synthesis. Telithromycin binds to the subunit 50S of the bacterial ribosome, and thus inhibits the translocation of peptides. Telithromycin has over 10 times higher affinity to the subunit 50S than erythromycin. In addition, telithromycin binds simultaneously in to two domains of 23S RNA of the ribosomal subunit 50S, where older macrolides bind only in one. Telithromycin can also inhibit the formation of ribosomal subunits 50S and 30S.

Pharmacokinetics Unlike erythromycin, telithromycin is acid-stable and can therefore be taken orally without being protected from gastric acids. It is fairly rapidly absorbed, and diffused into most tissues and phagocytes. Due to the high concentration in phagocytes, telithromycin is actively transported to the site of infection. During active phagocytosis, large concentrations of telithromycin is released. The concentration of telithromycin in the tissues much higher than in plasma.

Metabolism It is metabolized mainly in the liver, the main elimination route being the bile, a small portion is also excreted into the urine. About one third is excreted unchanged into the bile and urine, the biliary route being favoured. Telithromycin's half-life is approximately 10 hours

Side effects Most common side-effects are gastrointestinal; diarrhoea, nausea, abdominal pain and vomiting. Headache and disturbances in taste also occur. Less common side-effects include palpitations, blurred vision and rashes.

Antibiotics may also be classed as bactericidal (killing bacteria) or bacteriostatic (stopping bacterial growth and multiplication). Bacteriostatic drugs are effective because bacteria that are prevented from growing will die off after a time or be killed by the defence mechanisms of the host. The tetracyclines and the sulphonamides are among the bacteriostatic antiobiotics. Antibiotics that damage the cell membrane cause the cell's metabolites to leak out, eventually killing the organism. These compounds, including penicillins and cephalosporins, are therefore classed as bactericidal. Penicillins are the oldest group of antibiotics.

They are bactericidal, inhibiting formation of the cell wall by mechanical action. There are four types of penicillins: the narrow-spectrum penicillin-G types, ampicillin and its relatives, the penicillinase-resistants, and the antipseudomonal penicillins. Penicillin-G types are effective against gram-positive strains of streptococci, staphylococci, enterococci, and meningococci and are used to treat such diseases as syphilis, gonorrhoea, meningitis, anthrax, and yaws. The related penicillin V is used for respiratory infections. Ampicillin and amoxycillin have a range of effectiveness similar to that of penicillin-G types, with a slightly broader spectrum, including the gram-negative bacteria. Ampicillin and its relatives are effective against typhoid fever, bronchitis, urinary tract infections, pneumonia, meningitis, and bacteraemia. The penicillinase-resistants are penicillins that combat bacteria that have developed resistance to penicillin G. The aminoglycosides are penicillins that fight infections caused by gram-negative Pseudomonas bacteria, a particular problem in hospitals. h, k, b, h, j. These penicillins are administered as a prophylactic to patients with compromised immune systems, who are at risk from gram-negative infections. Side-effects of the penicillins, while relatively rare, can include immediate and delayed hypersensitivity—specifically, skin rashes, fever, and anaphylactic shock (abnormal reaction to the drug). Ampicillin can produce more side-effects than the penicillins; these primarily include nausea, vomiting, and diarrhoea. Amoxycillin has fewer adverse reactions.

Linezolid is a synthetic systemic antibiotic drug.

It was the first commercially available oxazolidinone antibiotic and is usually reserved for the treatment of serious bacterial infections where older antibiotics have failed due to antibiotic resistance. Conditions such as skin infections or nosocomial pneumonia where methicillin or penicillin resistance is found are indicators for linezolid use. Compared to the older antibiotics it is quite expensive.

The drug works by inhibiting the initiation of bacterial protein synthesis; it is the only antibiotic to work in this manner. That and its synthetic nature raised hopes that bacteria would be unable to develop resistance to it and also remove the chance of cross-resistance. (However, in 1997 Staphylococcus aureus was first identified in Japan as being resistant to linezolid.) Linezolid is effective against gram-positive pathogens, noyably E. faecium, S. aureus, S. agalactiae, S. pneumoniae, and S. pyogenes. It has almost no effect on gram-negative bacteria and is only bacteroistatic against most enterococcus species.

The oxazolidinone class was discovered by researchers at EI duPont de Nemours and reported in 1987. Pharmacia Corporation developed linezolid and FDA approval was granted in April 2000. It is sold in the US under the tradename Zyvox in either tablet form, oral suspension powder, or in an inactive medium for intravenous injection.

Side effects include rashes, loss of appetite, diarrhea, nausea, constipation and fever. A small number of patients will incur a severe allergic reaction, or tinnitis, or pseudomembranous colitis, or thrombocytopenia. Linezolid is a weak monoamine oxidase inhibitor (MAOI) and cannot be used with tyramine containing foods or pseudoephedrine.

Its chemical name is S-N-[[3-[3-Fluoro-4-(4-morpholinyl)]phenyl]-2-oxo-5-oxazolidinyl]methyl-acetamide and empirically the compound is C16H20FN3O4.

Polymyxins are cationic detergent antibiotics, with a general structure of a cyclic peptide with a long hydrophobic tail. They disrupt the structure of the bacterial cell membrane by interacting with its phospholipids. Polymyxins have a bactericidal effect on Gram-negative bacilli, especially on pseudomonas and coliform organisms. Polymyxin antibiotics are highly neurotoxic and nephrotoxic, and very poorly absorbed from the gastrointestinal tract.

Colistin (polymyxin E) is a polymyxin antibiotic produced by certain strains of Bacillus polymyxa var. colistinus. Colistin is a mixture of cyclic polypeptides colistin A and B. Colistin is effective against Gram-negative bacilli, except Proteus.

Administration Colistin is used as a sulphate or as sulphomethylated form, colistimethate. Colistin sulphate tablets are used to treat intestinal infections, or to suppress colon flora. Colistin sulphate is also used as topical creams, powders, and otic solutions. Colistimethate is used for parenteral administration, and also as an aerosol to treat pulmonary infections.

Mode of action Colistin is polycationic and has both hydrophobic and lipophilic moieties. These interact with the bacterial cytoplasmic membrane, changing its permeability. This effect is bactericidal.

Pharmacokinetics The absorption of colistin from the gastrointestinal tract is very poor. The main elimination route of colistin is through renal excretion.

Quinolones or fluoroquinolones are a group of broad-spectrum antibiotics.

Fluoroquinolone antibiotics are highly potent and considered relatively safe. However, they can have potentially troublesome side effects. For example, case reports have implicated their use in rare instances of tendon damage, especially when administered with a systemic corticosteroid.

Mechanism Quinolones act by inhibiting the bacterial DNA gyrase enzyme.

Ciprofloxacin is the generic international name for the synthetic antibiotic manufactured and sold by Bayer Pharmaceutical under the brand name Cipro® (and other brand names in other markets, e.g. veterinary drugs), belonging to a group called fluoroquinolones. Ciprofloxacin is bactericidal and its mode of action depends on blocking of bacterial DNA replication by binding itself to an enzyme called DNA gyrase, which allows the untwisting required to replicate one DNA double helix into two. Notably the drug has 100 times higher affinity for bacterial DNA gyrase than for mammalian.

Ciprofloxacin is a broad-spectrum antibiotic that is active against both Gram-positive and Gram-negative bacteria.

Enterobacteriaceae Vibrio Hemophilus influenzae Neisseria gonorrhoeae Neisseria menigitidis Moraxella catarrhalis Brucella Mycoplasma Campylobacter Helicobacter pylori Mycobacterium intracellulare Legionella sp. Pseudomonas aeruginosa Bacillus anthracis - that causes anthrax Weak activity against:

Streptococcus pneumoniae No activity against:

Bacteroides Burkholderia cepacia Enterococcus faecium and others The major adverse effect seen with use of is gastrointestinal irritation, common with many antibiotics. Because of its general safety, potency and broad spectrum activity, ciprofloxacin was initially reserved as a 'last-resort' drug for use on difficult and drug-resistant infections. As with any antibiotic, however, increasing time and usage has led to an increase in ciprofloxacin-resistant infections, mainly in the hospital setting. Also implicated in the rise of resistant bacteria is the use of lower-cost, less potent fluoroquinolones, and the widespread addition of ciprofloxacin and other antibiotics to the feed of farm animals, which leads to greater and more rapid weight gain, for reasons which are not clear.

Label information The drug is available for oral and parenteral use. It is used in lower respiratory infections (pneumonias), urinary tract infections, STDs, septicemias, Legionellosis and atypical Mycobacterioses.

It is contraindicated in children, pregnancy, and epilepsy.

Ciprofloxacin can