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 cause photosensitivity reactions and can elevate plasma theophylline levels to toxic values. It can also cause constipation and sensitivity to caffeine.

Dosage in respiratory infections is 500-1500 mg a day in 2 doses.

Cipro is coded as J01MA in ATC classification.

Business aspects The discovery and development of ciprofloxacin is that rare case of an actual groundbreaking new drug development, opening up an entire new class of antibiotics for further research, development, and marketing. Even more remarkable, it seems to be a case where the first drug discovered of this class remains the 'gold standard' in terms of efficacy, with the other drugs developed by other pharmaceutical companies relegated to 'me-too' status and forced to compete on the basis of lower cost.

Encouraged by the magnitude of this success, as well as the influx of cash, Bayer Pharmaceutical embarked on a plan to remake itself from a minor pharmaceutical manufacturer into a major player in the international pharmaceutical business, with a lock on the antibiotic field. Unfortunately, a combination of the tendency for antibiotics to be viewed as a commodity and prescribed on the basis of lowest cost, Bayer's inability to follow up with another 'blockbuster' discovery, and a general downturn in the international pharmaceutical business forced Bayer into a major downsizing in 2000-2001. Faced with the imminent expiration of its patent rights to ciprofloxacin in the early 2000's and the predictable loss of market share to generic ciprofloxacin, Bayer has resorted to the usual strategy of pharmaceutical companies in such a situaton; focus on the development and patenting of new variations of the old drug (i.e. pediatric ciprofloxacin, intravenous ciprofloxacin, once-a-day ciprofloxacin, etc.), which will have the side effect of extending the patent on the original drug.

"Cipro" became a household word during the anthrax mail attacks after the destruction of the World Trade Center. Unfortunately, Bayer not only took a severe financial blow from the costs involved in rapidly increasing production of the drug to be sold to the government at far below market price, but ironically was then portrayed in the press as 'War Profiteers', rather than contributors to the safety of the public in the "War on Terror".

Cephalosporin Like the penicillins, cephalosporins have a β-lactam ring structure that interferes with synthesis of the bacterial cell wall and so are bactericidal. Cephalosporins are more effective than penicillin against gram-negative bacilli and equally effective against gram-positive cocci. Cephalosporins are used to treat strains of meningitis and as a prophylactic for orthopaedic, abdominal, and pelvic surgery. They tend to be more expensive than the penicillins, although their low risk factor recommends their usage.

Because of their greater effectiveness against gram-negative bacteria, the cephalosporins are favoured prophylactics. Rare hypersensitive reactions from the cephalosporins include skin rash and, less frequently, anaphylactic shock. Streptomycin is the oldest of the aminoglycosides and, after penicillin, the most commonly administered antibiotic.

The aminoglycosides are narrow-spectrum antibiotics, inhibiting bacterial protein synthesis in gram-negative bacilli and staphylococci. They are sometimes used in combination with penicillin. All of the members of this group—particularly neomycin—tend to be more toxic than other antibiotics. Rare adverse effects associated with prolonged use of aminoglycosides include damage to the vestibular region of the ear, hearing loss, and kidney damage. Tetracyclines are bacteriostatic, inhibiting bacterial protein synthesis. They are broad-spectrum antibiotics effective against strains of streptococci, gram-negative bacilli, rickettsia (the bacteria that cause typhoid fever), and spirochaetes (the bacteria that cause syphilis). They are also used to treat acne, pelvic inflammatory disease, urinary tract infections, bronchitis, and Lyme disease. b, d, l, a, e. Because of their wide range of effectiveness, tetracyclines can sometimes upset the balance of resident bacteria that are normally held in check by the body's immune system, leading to secondary infections, such as thrush, in the vagina, for example. Tetracycline use is now limited because of the increase of resistant bacterial strains.

Ofloxacin sold under the brand name Floxin in the US. It is a quinolone antibiotic and similar in structure to levofloxacin. It is an alternative treatment to ciprofloxacin for anthrax.

Levofloxacin is relatively new fluoroquinolone antibiotic, marketed by Ortho-McNeil under the brand name Levaquin. Chemically, Levofloxacin is the S-enantiomer (L-isomer) of ofloxacin.

Levofloxacin is effective against a number of gram-positive and gram-negative bacteria. Because of its broad spectrum of action, levofloxacin is frequently prescribed in hospitals for pulmonary infections before the specific causal organisim is known. Once the causal organisim is known, levofloxacin is discontinued and the patient is given a narrow-spectrum antibiotic.

Sulfonamides, also known as sulfa drugs, are synthetic antimicrobial agents derived from sulfonic acid. In bacteria, these drugs are competitive inhibitors of para-aminobenzoic acid (PABA), a substrate of the enzyme dihydropteroate synthetase. This reaction is necessary in these organisms for the synthesis of folic acid.

The first sulfonamide was trade named prontosil. The first experiments with prontosil began in 1932 by the German chemist Gerhard Domagk, and the results were published in 1935 (after his employer, I. G. Farben, had obtained a patent on the compound). Prontosil was a red azo dye, and in mice had a protective action against streptococci. It had no effect in the test tube, and only exerted an antibacterial effect in the live animal itself. And, with war on the horizon, there was interest among the Allies to break the German patent.

Soon it was discovered (1936) that prontosil's active agent was a smaller, more effective compound known as sulfanilamide:

Sulfanilamide had a central role in preventing infection during World War II. American soldiers were issued a first aid kit containing sulfa powder and were told to sprinkle sulfa on any open wound. During the years 1942 to 1943, German/Nazi Doctors conducted sulfanilamide medical experiments on 74 Polish political prisoners in women's concentration camp in Ravensbrück.

An inadvertently toxic preparation of sulfanilamide also had a central influence on the US Food and Drug Administration. A preparation called Elixir Sulfanilamide contained ethylene glycol as a solvent, which is toxic. This preparation killed over one hundred people, mostly children, and led to the passage of the 1938 Food, Drug, and Cosmetic Act.

Many thousands of permutations of the sulfanilamide structure have been created since its discovery (by one account, over 5400 permutations by 1945), usually by the substitution of another functional group for a single amide hydrogen.

Certain sulfonamides (sulfadiazine or sulfamethoxazole) are sometimes mixed with the drug trimethoprim, which acts against dihydrofolate reductase.

Sulfa allergies are common enough that many medications are labeled as containing sulfonamides for this reason.

Tetracycline is an antibiotic produced by the streptomyces bacterium, indicated for use against many bacterial infections. It is sold under the brand names Tetralysal 300®, Panmycin®, Brodspec® and Tetracap®, among others. It is also used to produce several semi-synthetic derivatives, which are known as the Tetracyclines.

History Tetracycline was first discovered by Lloyd Conover in the research departments of Pfizer. The patent for Tetracycline was first issued in 1955 (patent number 2,699,054). Tetracycline sparked the development of many chemically altered antibiotics and in doing so has proved to be one of the most important discoveries made in the field of antiobiotics.

Mechanism and Resistance Tetracycline inhibits cell growth by inhibiting translation. It binds to the 30S ribosomal subunit and prevents the amino-acyl tRNA from binding to the A site of the ribosome. The binding is reversible in nature.

Cells become resistant to tetracyline by at least two mechanisms: efflux and ribosomal protection. In efflux, a resistance gene encodes a membrane protein that actively pumps tetracycline out of the cell. This is the mechanism of action of the tetracycline resistance gene on the artificial plasmid pBR322. In ribosomal protection, a resistance gene encodes a protein which binds to the ribosome and prevents tetracycline from acting on the ribosome.

Contraindications Tetracycline use should be avoided during pregnancy and in the very young (less than 6 years) because it will result in permanent staining of teeth causing an unsightly cosmetic result.

Doxycycline is a tetracycline antibiotic that is commonly prescribed by medical doctors for infections and to treat acne. It may also be used to treat urinary tract infections, gum disease, and other bacterial infections such as gonorrhea and chlamydia. Doxycycline is also used commonly as a prophylactic treatment for infection by Bacillus anthracis (anthrax). It is also effective against Yersinia pestis and malaria.

Its chemical name is (4S,4aR,5S,5aR,6R,12aS)-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphthacenecarboxamide.

At subantimicrobial doses, doxycycline is an inhibitor of matrix metalloproteinases, and has been used in various experimental systems for this purpose.

Oxytetracycline is known as a broad-spectrum antibiotic due to its activity against such a wide range of infections.

Treats Oxytetracycline is a medicine used for treating a wide range of infections including infections of the lungs, urinary system, skin and eyes. It may also be used to treat sexually transmitted infections, infections caused by lice, rickettsial infections, cholera and plague. It is very occasionally used to treat leptospirosis, gas gangrene, and tetanus.

Ingredients Often administered orally in the form of 250gm Tablets. Oxytetracycline tablets contain magnesium, stearate, maize starch, propylene glycol, colloidal silica, sodium lauryl sulphate, E104, E110, E171, E463, E464, E553.

Chloramphenicol is an antibiotic that was derived from the bacterium Streptomyces venezuelae and is now produced synthetically. Chloramphenicol is effective against a wide variety of microorganisms, but due to serious side-effects (e.g., damage to the bone marrow, including aplastic anemia) in humans, it is usually reserved for the treatment of serious and life-threatening infections (e.g., typhoid fever). It is also used in eye drops or ointment to treat bacterial conjunctivitis.

Chloramphenicol stops bacterial growth by binding to the bacterial ribosome and inhibiting protein synthesis.

Resistance to chloramphenicol is conferred by the cat-gene. This gene codes for an enzyme called "chloramphenicol acetyltransferase" which inactivates chloramphenicol by covalently linking one or two acetyl groups, derived from acetyl-S-coenzyme A, to the hydroxyl groups on the chloramphenicol. The acetylation prevents chloramphenicol from binding to the ribosome.

Clindamycin is a lincosamide antibiotic. Clindamycin is a semisynthetic antibiotic and derived from lincomycin by the addition of chloride. Clindamycin is sold under brand names such as Dalacin and Cleocin. It is most effective against infections involving the following types of organisms:

Aerobic gram-positive cocci, including some members of the Staphylococcus, Streptococcus and Pneumococcus genera. Anaerobic gram-negative bacilli, including some members of the Bacteroides and Fusobacterium genera. It is used primarily to treat infections caused by susceptible anaerobic bacteria. Such infections might include respiratory infections, septicemia and peritonitis. In penicillin allergic patients clindamycin may be used to treat susceptible aerobic infections as well. It is also used to treat bone-infections caused by Staphylococcus aureus.

Clindamycin is commonly administered in capsules as hydrochloride or in oral suspension as palmitate hydrochloride. It is also available for intravenous injection as phosphate. In topical preparations clindamycin is as hydrochloride or phosphate.

Mechanism of action Clindamycin has a bacteriostatic effect. Clindamycin interferes with bacterial protein synthesis, in a similar way as erythromycin and chloramphenicol, by binding to the 50S subunit of the bacterial ribosome. This causes antagonism if administered simultaneously and possible cross-resistance.

Pharmacokinetics Almost all of orally administered clindamycin is absorbed from the gastro-intestinal tract, and it is widely distributed throughout the body, excluding the central nervous system. Clindamycin phosphate, as injection, is inactive, but it is rapidly hydrolysed in the blood to active clindamycin. High concentrations of clindamycin can be found in the bile (up 100 times higher than in the plasma). Adequate concentrations can also be found in the bone, and there is also active uptake into leucocytes.

Metabolism Most of clindamycin is metabolised in the liver, and some of its metabolites are active, such as N-demethyl and sulphoxide-metabolites, and some are inactive. Clindamycin's half-life is 21 hours. Both active clindamycin and its metabolites are excreted primarily in the urine and some in the bile.

Side effects Common side effects are mainly gastrointestinal disturbances. Clindamycin can cause a potentially lethal condition, pseudomembranous colitis, which is caused by Clostridium difficile, a clindamycin resistant bacteria.

Fusidic acid is an antibacterial antibiotic used particularly for eye infections. It works by interfering with bacterial protein synthesis, specifically by preventing the translocation of the elongation factor G (EF-G) from the ribosome, although it works only on gram-positive bacteria such as Staphylococcus aureus, Streptococcus and Corynebacterium minutissimum. It was first isolated in 1962 from the fungus Fusidium coccineum, and later from Mucor ramannianus and Isaria kogana.

It is delivered as an ointment, a cream or eye drops.

Brand names Fusidin (of Leo in Canada) Fucidin Fucithalmic (of Leo in UK and Denmark)

Trimethoprim is a bacteriostatic antibiotic mainly used in the prophylaxis and treatment of urinary tract infections (cystitis). It belongs to the class of chemotherapeutic agents known as dihydrofolate reductase inhibitors. Trimethoprim was formerly marketed by GlaxoWellcome under trade names including Proloprim®, Monotrim® and Triprim®; but these trade names have been licensed to various generic pharmaceutical manufacturers.

Trimethoprim acts by interfering with the action of bacterial dihydrofolate reductase, inhibiting synthesis of tetrahydrofolic acid. Folic acid is an essential precursor in the de novo synthesis of the DNA nucleosides thymidine and uridine. Bacteria are unable to take up folic acid from the environment (i.e. the infection host) thus are dependent on their own de novo synthesis - inhibition of the enzyme starves the bacteria of two bases necessary for DNA replication and transcription.

Co-trimoxazole Trimethoprim is commonly used in combination with sulfamethoxazole, a sulfonamide antibiotic, which inhibits the an earlier step in the folate synthesis pathway (see diagram above). This combination, known as co-trimoxazole, results in a synergistic antibacterial effect by inhibiting successive steps in folate synthesis. Its use has been declining due to reports of sulfamethoxazole bone marrow toxicity.

Clinical indications Trimethoprim, used as monotherapy, is indicated for the prophylaxis and treatment of urinary tract infections (cystitis). Co-trimoxazole, owing to its greater efficacy, is indicated for a wider range of infections. For example, it is used as prophylaxis in patients at risk for Pneumocystis carinii pneumonia (e.g. AIDS patients and those with some hematological malignancies), as therapy in Whipple's disease and certain other infections.

The macrolides are bacteriostatic, binding with bacterial ribosomes to inhibit protein synthesis. Erythromycin, one of the macrolides, is an extremely safe antibiotic with minimal adverse effects. Erythromycin is effective against gram-positive cocci and is often used as a substitute for penicillin against streptococcal and pneumococcal infections. Other uses for macrolides include diphtheria and bacteraemia. Side-effects may include nausea, vomiting, and diarrhoea; infrequently, there may be temporary auditory impairment. The sulphonamides are synthetic bacteriostatic, broad-spectrum antibiotics, effective against most gram-positive and many gram-negative bacteria.

However, because many gram-negative bacteria have begun developing resistance to the sulphonamides, these antibiotics are now used only in very specific situations, including treatment of urinary tract infection, against meningococcal strains, and as a prophylactic (preventive treatment) for rheumatic fever.

Side-effects may include disruption of the gastrointestinal tract and hypersensitivity. The production of a new antibiotic is lengthy and costly. First, the organism that makes the antibiotic must be identified and the antibiotic tested against a wide variety of bacterial species. Then the organism must be grown on a scale large enough to allow the purification and chemical analysis of the antibiotic and to demonstrate that it is unique. This is a complex procedure because there are several thousand compounds with antibiotic activity that have already been discovered, and these compounds are repeatedly rediscovered. After the antibiotic has been shown to be useful in the treatment of infections in animals, larger-scale preparation can be undertaken. Commercial development requires a high yield and an economic method of purification. i, e, g, j, f. Extensive research may be needed to increase the yield by selecting improved strains of the organism or by changing the growth medium. The organism is then grown in large steel vats, in submerged cultures with forced aeration. The naturally fermented product may be modified chemically to produce a semi-synthetic antibiotic. After purification, the effect of the antibiotic on the normal function of host tissues and organs (its pharmacology), as well as its possible toxic actions (toxicology), must be tested on a large number of animals of several species. In addition, the effective forms of administration must be determined.

The discovery of antibiotics has been described as the greatest life-saving technological development in the history of modern medicine. Despite the frequent success of antibiotics in reversing life-threatening infections, infectious diseases remain a serious problem for elderly people. At a time when medical technologies can support body functions almost indefinitely, severe infection is still a challenge when infections account for approximately 30 percent of all deaths in the elderly population.

Although antibiotics are usually effective in the treatment of infections, these drugs cannot cure underlying diseases or disabling conditions that are common among elderly persons. In some persons, a life-threatening infection is superimposed on a terminal illness or an incurable, severely debilitating, chronic disease. Some healthcare providers believe that in some cases the use of antibiotics to treat an infection prolong the dying process or prolongs the patient's suffering unnecessarily.

Some of the life-threatening infections that commonly affect elderly people are: bacterial pneumonia, urinary tract infections, infected decubitus ulcers (bed or pressure sores), and introgenic infections that sometimes result from the use of medical devices. Any local infection in a seriously ill older person, however, can rapidly spread and become life-threatening.

Various risk factors make older people vulnerable to infection and include:

Hospitalization -- People are exposed to a large number of agents that can cause infections. Nosocomial (hospital-acquired) infections are often fatal, in part because they are frequently caused by agents that are resistant to antibiotics.

Communal living -- The common use of urinary catheters and other factors often associated with nursing home care, foster infections.

Diminished immune function -- Aging, various diseases, some medical treatments, and inadequate food and fluid intake that may result from poverty, depression, forgetfulness, mobility impairments, illness, or medical treatments that decrease appetite can result in reduced immune function.

Life-sustaining medical devices -- Mechanical ventilators, dialysis equipment, and other devices used to provide total parenteral nutrition can increase the risk of infections. Antibiotics are a large set of drugs use to cure or control numerous bacterial, viral, and fungal infections, including minor ones. Different families of antibiotics have been developed for use in combatting different types of infections. Antibiotics may be administered topically, orally, intravenously, or intramuscularly, in discrete doses or continuously. All antibiotics are potentially life-sustaining.

Except for antibiotics, none of the five life-sustaining technologies discussed in this article cure the underlying condition that precipitated its use. Thus, among patients who receive these interventions and survive, health status and functional capacity vary widely. While some patients regain adequate natural function of the affected organ, others become permanently dependent on the life-sustaining technology (and they may be simultaneously dependent on more than one life-sustaining technology). They may require continuous medical care and, often, other forms of assistance.

Antibiotics generally are successful in combating most types of infections, with patients showing improvement within a few hours or days, and complete cure within a few days or weeks. With older persons, the outcome of antibiotic treatment for life-threatening infections are often unpredictable.

However, antibiotic therapy is especially important for chronically ill older people receiving long-term mechanical ventilation, dialysis, or nutritional support. Without antibiotic treatment of the iatrogenic infections often associated with these technologies, it would be impossible to restore these patients to a clinically stable condition. Antibiotics enable these other technologies to sustain lives.

Antibiotics are the least complex and least expensive life-sustaining technologies. Because physicians consider antibiotics ordinary or standard treatment, their decisions to use them in the treatment of life-threatening infections are often automatic. Clinic criteria, rather than patient's or surrogate's wishes, are often their primary considerations. In addition, many elderly patients being considered for life-sustaining antibiotic treatment are severely debilitated and incapable of making treatment decisions. Decisionmaking aids like the living will are rarely of use to these people, who often have been incapacitated for a long time and are unlikely to have given specific prior directives regarding their care.

The outcomes of life-sustaining antibiotic treatment range from complete cure to death. Antibiotics are usually effective in curing infections. However, they can neither eliminate nor alleviate preexisting illness in chronically, critical, or terminally ill or severely debilitated elderly people. Many health care providers believe that antibiotic treatment is always appropriate when an active infection is present.

Despite this strong presumption in favor of using antibiotic therapy, some health care providers and other believe that there are circumstances in which it is justifiable to withhold life-sustaining antibiotic treatment. For example, one physician told about his 96-year-old mother who experienced two strokes a week apart and developed pneumonia. The woman's children asked the hospital staff not to treat the pneumonia, but the staff insisted they could not "do nothing," and she was given antibiotics. She ended up in a nursing home in a semivegetative state, she lost her functional and mental independence. Everything she wanted to avoid has happened to her.

The historical scourge known as the bubonic plague killed up to one-third of Europe's population in the 1300s. But in modern times, it has been controlled handily with the help of antibiotic drugs such as streptomycin, gentamicin and chloramphenical.

That is, until 1995, when a plague infection in a 16-year-old boy from Madagascar failed to respond to the usual antibiotic treatments. This first documented case of an antibiotic-resistant plague, reported in the September 1997 New England Journal of Medicine, eventually succumbed to another antibiotic.

In the United States and globally, many other infectious germs, including those that cause pneumonia, ear infections, acne, gonorrhea, urinary tract infections, meningitis, and tuberculosis, can now outwit some of the most commonly used antibiotics and their synthetic counterparts, antimicrobials. According to the Mayo Clinic in Rochester, Minn., drug resistance may have contributed to the 58 percent rise in infectious disease deaths among Americans between 1980 and 1992.

Antibiotic resistance isn't a new problem; resistant disease strains began emerging not long after the discovery of antibiotics more than 50 years ago. Penicillin and other antibiotics, which were initially viewed as miracle drugs for their ability to cure such serious and often life-threatening diseases as bacterial meningitis, typhoid fever, and rheumatic fever, soon were challenged by some defiant strains.

"What's different now," explains David Bell, M.D., an expert on antimicrobial resistance with the national Centers for Disease Control and Prevention, "is that we've reached a situation where it's no longer an isolated problem of this bug or that bug; virtually all important human pathogens treatable with antibiotics have developed some resistance."

Despite the frightening trend, most people aren't likely to encounter a "superbug" that can outsmart all antibiotics, says Mark Goldberger, M.D., director of the Food and Drug Administration's division of special pathogen and immunologic drug products. "For the average person walking around on the street, the risk at the moment remains low."

Still, as one antibiotic's effectiveness wanes, doctors are forced in many cases to rely on more expensive and toxic drugs. Resistance is "a big problem and growing," says Linda Tollefson, director of surveillance and compliance in FDA's Center for Veterinary Medicine. "You're dealing with living microbes that have shown an incredible ability to accommodate antibiotics and come out winning. We have no idea what they are going to do next. Our fear is that we're seeing the tip of the iceberg."

To stop infectious germs from gaining ground, experts the world over, including doctors and scientists from FDA, CDC, and the World Health Organization, have been focusing since 1995 on finding ways to prolong the lives of antibiotics and to encourage drug companies to develop new "miracle drugs."

Antibiotics may be topical—applied to the surface of the skin, eye, or ear in the form of ointments or creams. They may be oral—given by mouth, and either allowed to dissolve in the mouth or be swallowed, in which case they are absorbed into the bloodstream through the intestines. Antibiotics may also be parenteral—injected intramuscularly, intravenously, or subcutaneously; antibiotics are administered parenterally when fast absorption is required. In Britain, once these steps have been completed, the manufacturer may apply for a Clinical Trial Exemption from the Medicines Control Agency (MCA). If approved, the antibiotic can be tested on a few healthy volunteers for toxicity, tolerance, absorption, and excretion (Phase 1).

If subsequent tests on small numbers of patients are successful (Phase 2), the drug can be tested on a larger group, usually in the hundreds (Phase 3). Finally a New Drug application can be filed with the MCA, and, if a Marketing Authorization is granted, the drug can be used generally in clinical medicine. These procedures, from the time the antibiotic is discovered in the laboratory until it completes clinical trial, usually extend over several years. Emerging infectious diseases, such as hantavirus pulmonary syndrome and human granulocytic ehrlichiosis (HGE—which is related to Lyme disease) in parts of the United States and the reappearance of older ones, such as TB, polio, and diphtheria—as well as Ebola fever in West Africa and dengue fever and dengue haemorrhagic fever in Latin America—have put paid to the idea held since the 1950s that antibiotics can cure all infectious disease. Re-emerging diseases—those making a comeback after a period of disappearance either because of drug-resistant strains of bacteria, continued decline in public health, or lowered immunity (often due to AIDS) in the victims—include TB, cholera, and syphilis. Other factors such as overcrowding, greater population mobility and resettlement, social collapse (such as in Eastern Europe, where diphtheria has reappeared), intercontinental travel, and climate changes have all increased the spread of infectious diseases in both the developing and developed world. j, a, f, j, d. Equally important has been a decline in public health measures in parts of the developed world, such as lack of access to childhood vaccination programmes, and the withdrawal of funds for research into diseases like TB.

Experts say that doctors are sometimes quick to prescribe antibiotics for all sorts of symptoms, even though antibiotics work only against bacterial infections, not viruses such as the flu or the common cold. More than 50 million of the 150 million antibiotic prescriptions written each year for patients outside of hospitals are unnecessary, according to a recent CDC study. (See chart.)

Sometimes, doctors lack knowledge about the symptoms and natural course of respiratory illnesses, which contributes to overuse, according to a CDC editorial in the Sept. 17, 1997, Journal of the American Medical Association. Also, many doctors have told CDC they sometimes write prescriptions simply to meet patient demands.

Patients therefore must take some of the responsibility for the overprescribing problem, according to Stuart Levy, M.D., director of Tufts University's Center for Adaptation Genetics and Drug Resistance. "Patients have been left out of the formula. Overuse of antibiotics was felt to be a physicians' problem when it is really as much a patient problem."

Patients can do their part to help curb resistance:

Don't demand an antibiotic when the health-care provider determines one isn't appropriate.

Finish each prescription. Even when the symptoms of an illness have disappeared, some bacteria may still survive and reproduce if the patient doesn't complete the course of treatment.

Don't take leftover antibiotics or antibiotics prescribed for someone else. These antibiotics may not be appropriate for the current symptoms, and taking the wrong medicine could delay getting appropriate treatment and allow bacteria to multiply.

For more tips on proper antibiotic use, visit the Website of the Alliance for the Prudent Use of Antibiotics (www.healthsci.tufts.edu/apua/patient.htm).

Even when used carefully, all organisms can develop some resistance to antibiotics over time. "It is a perfectly natural phenomenon for a living organism to develop the means of survival in a hostile environment," wrote French microbiologist Jacques Acar in a 1997 article in World Health.

Preventing infection in the first place may therefore be the best defense against an antibiotic-resistant infection.

Frequent and thorough hand washing is one key to preventing the spread of infection. Good kitchen habits, such as storing foods at the proper temperature, washing fruits and vegetables thoroughly, and cooking foods completely, can also reduce the chance of getting a food-borne illness. (See "Can Your Kitchen Pass the Food Safety Test?" in the October 1995 FDA Consumer.)

WHAT IS AN ANTIBIOTIC? An antibiotic is any substance produced by a microorganism, i.e. bacteria or fungi, that it sends outside it's cell to harm or kill another microorganism(4). The benefit is easy to see. If an organism is able to produce chemicals that inhibit or kill other nearby organisms, it has an advantage in competing for local resources.

Technically, antibiotics are microbial or fungal products. But we are able to synthesize and mass produce these chemical substances in the laboratory to use against harmfull microorganisms in our environment. There is a distinction between natural and synthetic antibiotics, but in practice most drugs used to combat microbial and fungal infections are grouped under the general heading "antibiotics"(5).

Contrary to what many people believe, antibiotics are ineffective when it comes to treating a virus, such as the flu and most colds and coughs. In addition, medical journals report that taking antibiotics unnecessarily can kill sensitive bacteria while leaving resistant ones to grow and multiply. This can lead to the proliferation of antibiotic-resistant bacteria that may not respond to antibiotic treatment in the future.

A recent survey indicates that more than 60% of patients with viral upper respiratory infections receive an antibiotic as treatment. Unaware that they are ineffective, many patients request antibiotics from their doctors when the virus really just has to run its course.

"Consumers play a key role in their own healthcare, and we feel it is very important that they have the correct information," says NCL President Linda Golodner. "Hopefully, people will hear these radio spots during the cold and flu season and realize that not only are antibiotics not going to cure a viral infection, but that the inappropriate use of antibiotics can lead to the emergence of super-bacteria that will not respond to future treatment."

Robert Epstein, M.D., chief medical officer and senior vice president of Merck-Medco Managed Care, L.L.C., provided narration for the public service announcements, made possible through a grant from Merck-Medco. Merck-Medco manages prescription programs for more than 50 million Americans through the benefit plans of employers, unions, Blue-Cross/Blue-Shield groups and insurance companies. Merck-Medco also mailed information to 20,000 physicians who commonly prescribe antibiotics reminding them of the dangers of prescribing antibiotics for viral infections.

SAN FRANCISCO (Reuters) - The increased use of antibiotics in food animals is boosting the risk that dangerous "superbugs" resistant to drug treatment could be passed along to humans, scientists said Monday. "It's not just a single pig or a single cow. It's a whole food commodity issue," Michael Osterholm, CEO of the Infection Control Advisory Network, told a news conference at a scientific meeting here. "Red meat, white meat, produce any commodity stream can play a role."

Scientists both in Europe and the United States have raised questions over the treatment of food animals with antibiotics, which farmers use widely both to fight animal illness and as part of animal feed to promote growth.

The European Union banned four antibiotics used in animal feed last December, hitting multinational drug companies Rhone Poulec, Pfizer, Eli Lilly's Elanco Animal Health and Alpharma and potentially costing them hundreds of millions of dollars in lost sales.

In the United States, authorities have moved more slowly, with the Food and Drug Administration monitoring the veterinary use of antimicrobial drugs with an eye toward regulating those drugs seen most likely to create resistant bacteria which could lead to human illness.

KEY BACTERIA FOUND IN U.S.

Bacteria which shrugs off one of the most powerful known antibiotics - vancomycin -has been found in some U.S. chicken feed, and research on pigs, cows and chickens has revealed signs that drug-resistant strains of salmonella, campylobacter and other bacteria are also spreading through animal populations.

In a series of reports at the Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) here, scientists presented new findings indicating that the problem is growing more complex as governments try to assess how much of a threat dinner may really pose to public health.

In a study at the University of Antwerp, researchers found that samples of chickens, pigs and turkeys turned up "alarmingly high" anti-microbial resistance rates among strains of campylobacter bacteria, which are a major cause of human gastroenteritis and diarrhea.

"There is growing scientific evidence that the use of antibiotics in food animals leads to the development of resistant pathogenic bacteria that can reach humans through the food chain," the study's authors concluded. Another study at the University de la Rioja in Spain found a relatively high rate of antibiotic resistance in E.coli bacteria strains obtained from broiler chickens compared with those found in humans or their pets a difference the researchers said could be associated with the more widespread use of antibiotics in farm chickens.

This year, U.S. researchers in Minnesota reported a rise in human gastrointestinal illness caused by antibiotic-resistant campylobacter bacteria which they tied directly to the increase in quinolone-type antibiotics given to chickens.

PROBE SEEKS RISKS

Stephen Sundlof, director of the FDA's Center for Veterinary Medicine, said the agency is working with the Centers for Disease Control to determine the actual risks posed by antimicrobial use in farm animals and hoped to establish regulations aimed at limiting the use of drugs which might eventually lose effectiveness in treating human illness. The go-slow approach has pleased the makers of animal drugs, who say there simply is not enough evidence to back the idea that farm animals could become a stealth health threat.

"We would not agree to outright bans on these products. We need more data," said Richard Carnevale, a spokesman for the Animal Health Institute, an industry group. "We support prudent use (of antibiotics). We don't want to see precipitous action against products that are needed for animal treatment."

Antibiotics are powerful medicines used to treat bacterial infections. Bacteria are microscopic one-celled organisms. Some bacteria are beneficial and some are detrimental to human health. Antibiotics work by either inhibiting bacteria from reproducing or by breaking apart the cell walls of bacteria. Viruses are sub-microscopic organisms, strands of DNA or RNA that get inside human cells to cause damage. Antibiotics cannot affect sub-microscopic viruses.

The use of antibiotics is limited in the United Kingdom to prescription only medicine because bacteria have evolved defences against certain antibiotics. One of the main mechanisms of defence is inactivation of the antibiotic. This is the usual defence against penicillins and chloramphenicol, among others. Another form of defence involves a mutation that changes the bacterial enzyme affected by the drug in such a way that the antibiotic can no longer inhibit it. This is the main mechanism of resistance to the compounds that inhibit protein synthesis, such as the tetracyclines.

All these forms of resistance are transmitted genetically by the bacterium to its progeny. Genes that carry resistance can also be transmitted from one bacterium to another by means of plasmids, chromosomal fragments that contain only a few genes, including the resistance gene. Some bacteria conjugate with others of the same species, forming temporary links during which the plasmids are passed from one to another. If two plasmids carrying resistance genes to different antibiotics are transferred to the same bacterium, their resistance genes can be assembled on to a single plasmid. The combined resistances can then be transmitted to another bacterium, where they may be combined with yet another type of resistance. In this way, plasmids are generated that carry resistance to several different classes of antibiotic.

In addition, plasmids have evolved that can be transmitted from one species of bacteria to another, and these can transfer multiple antibiotic resistance between very dissimilar species of bacteria. The problem of resistance has been exacerbated by the use of antibiotics as prophylactics—intended to prevent infection before it occurs. Indiscriminate and inappropriate use of antibiotics for the treatment of the common cold and other common viral infections, against which they have no effect, removes antibiotic-sensitive bacteria and allows the development of antibiotic-resistant bacteria. Similarly, the use of antibiotics in poultry and livestock feed has promoted the spread of drug resistance and has led to the widespread contamination of meat and poultry by drug-resistant bacteria such as Salmonella. d, d, b, b, k. A Tuberculosis and Malaria Advertisement In the 1970s, TB was all but eradicated in the developed countries, although it was still prevalent in developing countries. Now its incidence is increasing, partly because of migration, poverty, and reduced public health provisions, but chiefly because of increased resistance of the tubercle bacillus to antibiotics, which can result from patients not completing the course of treatment. This can produce more complex drug-resistant strains of TB which are far more difficult to treat. In 1998 the rise of drug-resistant tuberculosis worldwide led the World Health Organization to declare a global emergency.

What's The Difference?

Bacterial infections typically cause the human body's immune system to create pus. This is white blood cells that help kill bacteria. Examples of these bacteria infections are ear infections (i.e., pus behind the eardrums), strep throat, urinary tract infections, and bacterial pneumonia.

Viruses, on the other hand, typically are the cause of colds an gastroenteritis. The body's response to viruses is mucus, phlegm, ulcerations, and vesicles as in chicken pox. Other examples of viral infections are the common cold, flu, and croup.

A Vitally Important Lesson

For doctors, it is very important not to use medicines when they are ineffective. The main reason for not using antibiotics "just in case" during a viral illness is the issue of resistant bacteria. New strains of bacteria have emerged. Every time an antibiotic is given, bacteria resistant to its effects may be left behind to create havoc another day. A different antibiotic might need to be prescribed for the next similar infection. So it is easy to see, if we over-use antibiotics, we may create a bacteria resistant to all known antibiotics, which has actually happened. The best way to protect a child from antibiotic-resistant bacteria is not to insist on an antibiotic when no bacterial infection is diagnosed.

Some further thoughts about the common cold are that a cold typically lasts 7-10 days in a child. It may or may not have an associated fever. In a cold, which is caused by a virus, the mucus in the nose typically changes through the course of the cold. Yellow-green discharge does not mean a bacterial infection. Remember, mucus and phlegm are typically viral.

Some bacteria, particularly strains of staphylococci, are resistant to so many classes of antibiotics that the infections they cause are almost untreatable. When such a strain, particularly antibiotic methicillin-resistant staphylococcus aureus (MRSA), invades a surgical ward in a hospital, it is sometimes necessary to close the ward altogether for a time. Similarly, plasmodia, the causative organisms of malaria, have developed resistance to antibiotics, while, at the same time, the mosquitoes that carry plasmodia have become resistant to the insecticides that were once used to control them. Consequently, malaria is once again rampant in parts of Africa, the Middle East, south-eastern Asia, and Latin America. Recommendations to avoid a worldwide crisis predicted by public health authorities are: better training of GPs to resist pressure from patients for antibiotics to treat trivial or viral infections; reduced public availability of antibiotics in some countries; better public awareness; phasing out of antibiotic growth promoters in animals; and a veterinary code of practice on the use of drugs vital to human medicine.

In 1936 the German pathologist Gerhard Johannes Paul Domagk, working in a Bayer laboratory, found that sulphonamidochrysoidine, a dyestuff branded as “Prontosil”, was effective against infection by streptococci. Puerperal sepsis, a disease which sometimes followed childbirth and often killed the mother, was caused by this micro-organism. It was shown that the active part of the Prontosil molecule was the sulphonamido radical, and this stimulated the industry's researchers to synthesize a number of new drugs known as sulphonamides, or “sulpha drugs”. Among these was M&B 693 (sulphapyridine), first made and tested in 1938 at May & Baker's laboratories in Dagenham, Essex. It was praised by Winston Churchill in 1942, for securing his recovery from pneumonia.

The discovery of penicillin by Alexander Fleming in 1928, and his suggestion that it could be used to treat some bacterial infections, is well known. However, such use was not seriously considered until 1940, when Howard Florey and the German refugee chemist Ernst Chain succeeded in making and testing it in a usable form. Recognizing its use for war wound treatment, a number of companies in the United Kingdom set about making it from Penicillium cultures grown in batteries of glass bottles. Quantities produced were insufficient, so Florey went to the United States to persuade US pharmaceutical companies to make it. After the war all three men received Nobel Prizes.

The Brooklyn chemical firm Pfizer made citric acid by the deep fermentation of molasses. After much research they adapted the process to produce penicillin. With the cooperation of US pharmaceutical companies they produced enough doses for distribution to the Allied forces in time for D-Day and the subsequent campaign.

Penicillin was made generally available throughout the world after the war. It was followed by the discovery of other substances active against a variety of infections. These substances were known collectively as antibiotics. Notable among them was streptomycin, discovered by Selman A. Waksman and developed in the laboratories of the US pharmaceutical firm Merck & Co., of New Jersey. Used together with the antibacterial chemicals isoniazed and para-aminosalicylic acid it cured tuberculosis, caused by the tubercle bacillus, which killed some 20,000 young people every year in Britain alone. This treatment and the use of BCG vaccine—the name of which incorporates the initials of its French wartime inventors, the bacteriologists Albert Calmette and Camille Guérin—for a time almost completely eradicated the disease in the West, but it has subsequently reappeared (see Tuberculosis: The Re-emergence of TB).

The effective action of isoniazed was coincidentally discovered in the laboratories of Squibb in the United States and Hoffmann-La Roche in Switzerland. Unfortunately for both companies the substance had already been synthesized in 1911 as a “chemical curiosity”, so no patent was available to repay the cost of their research and development.

Antibiotics (Greek anti,"against;"bios,"life") are chemical compounds used to kill or inhibit the growth of infectious organisms. Originally the term antibiotic referred only to organic compounds, produced by bacteria or molds, that are toxic to other microorganisms. The term is now used loosely to include synthetic and semisynthetic organic compounds. Antibiotic refers generally to antibacterials; however, because the term is loosely defined, it is preferable to specify compounds as being antimalarials, antivirals, or antiprotozoals. 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, gonorrhea, tetanus, and scarlet fever. Another antibiotic, streptomycin, has been used to combat tuberculosis.

Although the mechanisms of antibiotic action were not scientifically understood until the late 20th century, the principle 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 molds for topical treatment of infection. The first observation of what would now be called an antibiotic effect was made in the 19th century by French chemist Louis Pasteur, who discovered that certain saprophytic bacteria can kill anthrax bacilli. In the first decade of the 20th century, German physician 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 spirochetes, 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 Sir 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 some antimicrobial activity, but it is not clinically useful.

Penicillin, the archetype of antibiotics, is a derivative of the mold Penicillium notatum. Penicillin was discovered accidentally in 1928 by Fleming, who showed its effectiveness in laboratory cultures against many disease-producing bacteria. This discovery marked the beginning of the development of antibacterial compounds produced by living organisms. Penicillin in its original form could not be given by mouth because it was destroyed in the digestive tract and the preparations had too many impurities for injection. No progress was made until the outbreak of World War II stimulated renewed research and the British scientists Sir Howard Florey and Ernst Chain purified enough of the drug to show that it would protect mice from infection. Florey and Chain then used the purified penicillin on a human patient who had staphylococcal and streptococcal septicemia with multiple abscesses and osteomyelitis. The patient, gravely ill and near death, was given intravenous injections of a partly purified preparation of penicillin every three hours. Because so little was available, the patient's urine was collected each day, the penicillin was extracted from the urine and used again. After five days the patient's condition improved vastly. However, with each passage through the body, some penicillin was lost. Eventually the supply ran out and the patient died.

The first antibiotic to be used successfully in the treatment of human disease was tyrothricin, isolated from certain soil bacteria by American bacteriologist Rene 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 American biologist Selman Waksman and his associates, was, in its time, the major treatment for tuberculosis.

Most antibiotics act by selectively interfering with the synthesis of one of the large-molecule constituents of the cell–the cell wall or proteins or nucleic acids. Some, however, act by disrupting the cell membrane (see Cell Death and Growth Suppression below). Some important and clinically useful drugs interfere with the synthesis of peptidoglycan, the most important component of the cell wall. These drugs include the -lactam antibiotics, which are classified according to chemical structure into penicillins, cephalosporins, and carbapenems. All these antibiotics contain a -lactam ring as a critical part of their chemical structure, and they inhibit synthesis of peptidoglycan, an essential part of the cell wall. They do not interfere with the synthesis of other intracellular components. The continuing buildup 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 do not affect human cells because human cells do not have cell walls.

Many antibiotics operate by inhibiting the synthesis of various intracellular bacterial molecules, including DNA, RNA, ribosomes, and proteins. The synthetic sulfonamides are among the antibiotics that indirectly interfere with nucleic acid synthesis. Nucleic-acid synthesis can also be stopped by antibiotics that inhibit the enzymes that assemble these polymers–for example, DNA polymerase or RNA polymerase. Examples of such antibiotics are actinomycin, rifamicin, and rifampicin, the last two being particularly valuable in the treatment of tuberculosis. 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 the assembly of messenger RNA, thus causing its genetic message to be garbled. When these faulty messages are translated, the protein products are nonfunctional. 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; chloramphenicol prevents the linking of amino acids to the growing protein; and puromycin causes the protein chain to terminate prematurely, releasing an incomplete protein.

The production of a new antibiotic is lengthy and costly. First, the organism that makes the antibiotic must be identified and the antibiotic tested against a wide variety of bacterial species. Then the organism must be grown on a scale large enough to allow the purification and chemical analysis of the antibiotic and to demonstrate that it is unique. This is a complex procedure because there are several thousand compounds with antibiotic activity that have already been discovered, and these compounds are repeatedly rediscovered. After the antibiotic has been shown to be useful in the treatment of infections in animals, larger-scale preparation can be undertaken.

Commercial development requires a high yield and an economic method of purification. Extensive research may be needed to increase the yield by selecting improved strains of the organism or by changing the growth medium. The organism is then grown in large steel vats, in submerged cultures with forced aeration. The naturally fermented product may be modified chemically to produce a semisynthetic antibiotic. After purification, the effect of the antibiotic on the normal function of host tissues and organs (its pharmacology), as well as its possible toxic actions (toxicology), must be tested on a large number of animals of several species. In addition, the effective forms of administration must be determined. Antibiotics may be topical, applied to the surface of the skin, eye, or ear in the form of ointments or creams. They may be oral, or given by mouth, and either allowed to dissolve in the mouth or swallowed, in which case they are absorbed into the bloodstream through the intestines. Antibiotics may also be parenteral, or injected intramuscularly, intravenously, or subcutaneously; antibiotics are administered parenterally when fast absorption is required.

In the United States, once these steps have been completed, the manufacturer may file an Investigational New Drug Application with the Food and Drug Administration (FDA). If approved, the antibiotic can be tested on volunteers for toxicity, tolerance, absorption, and excretion. If subsequent tests on small numbers of patients are successful, the drug can be used on a larger group, usually in the hundreds. Finally a New Drug Application can be filed with the FDA, and, if this application is approved, the drug can be used generally in clinical medicine. These procedures, from the time the antibiotic is discovered in the laboratory until it undergoes clinical trial, usually extend over several years.

The development of antibiotics more than fifty years ago has saved millions of lives that would have been lost to infection. These drugs are some of our most potent weapons against disease. Unfortunately, they come with a price. Over the last twenty years, the number of infections resistant to antibiotics has mushroomed. We are now faced with the possibility that our antibiotics may become useless. This worries us and has led us to adopt a policy limiting antibiotic use to instances where it is truly needed. This chapter is designed to explain this policy and the reasons behind it.

First, it is important to know that there are two main causes of infection in children. The first is viruses. Viruses are very tiny living things that cause diseases such as colds, the flu, stomach flu, and many ear infections. They can sometimes cause more serious illnesses such as meningitis and pneumonia. Antibiotics DO NOT work against viruses. The other cause of infections is bacteria. These are also very tiny living things (but much bigger than viruses). They commonly cause illnesses such as pneumonia, meningitis, ear infections, urinary tract infections, Strep throat, sinusitis, and impetigo. Antibiotics do work against bacteria, but the problem is that many of these bacteria are now resistant to the antibiotics. That makes it difficult to treat some of these infections.

THE GOOD AND THE BAD ABOUT ANTIBIOTICS Antibiotics are drugs used to treat bacterial infections. They are one of the most important medical advances of the 20th century. When used properly, antibiotics can treat many very serious diseases such as pneumonia, tuberculosis, and typhoid. However, when used improperly, antibiotics can actually be harmful. UNDERSTANDING INFECTIONS: VIRAL OR BACTERIAL? There are two types of infections that your child may have: viral and bacterial. Viral infections are caused by viruses, tiny organisms that infect the body. Viruses cause a lot of the illnesses we're most familiar with, such as the common cold, sore throats, and coughs. In fact, 85% of sore throats are caused by viruses. Antibiotics should not be used to treat viral infections because they do not kill the virus and are useless in treating viral infections. Viral infections that cause the common cold and sore throat usually last about a week and must run their course before they go away. RESISTANT BACTERIA: HOW TO PROTECT YOUR CHILD The Centers for Disease Control and Prevention (CDC) recommends against using antibiotics for viral infections. Yet millions of unnecessary antibiotic prescriptions are written each year for colds, sore throats, and other common viral infections. This can lead to the development of resistant bacteria, sometimes called "superbugs." Superbugs are bacteria that are so strong they become resistant to antibiotics. These superbugs often multiply and may spread to other family members or the community, making these infections impossible to treat and control with ordinary antibiotics. In fact, superbugs can cause serious infections that may require hospitalization or may not be treatable at all. The more your child is given antibiotics unnecessarily, the greater the chance that he or she may become infected with resistant bacteria. Understanding this is the first step toward taking the best care of your child and your family.

Before resistance to antibiotics was noticed, the use of antibiotics had to become wide spread. Antibiotics are used to treat many bacterial disorders. They do so by selectively affecting the bacteria while leaving the human cells alone. This is an important feature that antibiotics must possess, because they would do little good if they killed the patient's cells along with the bacteria. Antibiotics have many different mechanisms of attack on the bacterial cells. In order to understand the resistance by the bacteria, the mechanism of attack from the antibiotic must first be understood.

Penicillin was the first antibiotic discovered in 1929. It was isolated from Penicillium notatum, a fungus. Penicillan is categorized as a b -lactam because of the b -lactam ring that is present in its chemical structure. It became commercially available in 1941 and was eventually isolated from P. chrysogenum since a better yield could be obtained. The first drug to become commercially available was prontosil and was used to fight murine streptococcal infection. A wave of antibiotic drugs with different mechanisms of attack against bacterial strains followed these two first antibiotics.

Penicillin stops bacterial cells reproduction by inhibiting the synthesis of a new cell wall, which is essential for the survival of the bacteria. Penicillin, as well as other b -lactams, inhibits the enzyme which places essential cross-links between the individual polymer strings of the cell wall. It does this specifically by using the b -lactam ring to irreversibly block the active site of the enzyme which catalyzes the reation, transpeptidase. This inhibition allows the bacteria to newly synthesize a cell wall and to elongate, but not divide. This is due to the lack of cross-linking which causes weak areas in the cell wall. These weak areas cause the bacteria to rupture. To see a movie of how penicillin works click here.

An important antibiotic class are the sulphonamides. The first sulphonamide discovered was prontosil which was found to be converted into sulphanilamide in vivo. Both of these compounds were found to have antibacterial activites and lead to the discovery of other drugs. Several other sulphaniamide antibiotics were synthesized by substituting the end groups with different chemical substituents. Sulphonamides were the first man-made drugs to be used commercially.

Sulphonamides are specific to bacteria because of their mode of action. They inhibit the biosynthesis of folic acid, which does not occur in mammalian cells. The sulphonamides compete with p-aminobenxoic acid that is incorporated into terahydropteroic acid, an essential step in the pathway for the synthesis of folic acid and therefore inhibits the pathway. Sulphonamides are only active against Gram-positive bacteria, but have been used successfully to treat pneumonia, osteomyelitis, furuncle, carbuncle and puerperal infections.

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Last modified: May 25, 2005