The term antibiotic is applied to drugs obtained from one group of micro-organisms (e.g. bacteria, fungi) that are used to kill another group of micro-organisms. Antibiotics may be antibacterial and/or antifungal. They are chemicals which stop the growth of micro-organisms (bacteriostatic) and/or eventually kill them (bactericidal).* Numerous antibiotics are available and they vary in their structure, action, effects and the type of bacteria which are sensitive to them. They are produced by various micro-organisms such as fungi and bacteria and have been obtained from moulds, soil and other sources. Those produced from moulds may be called biosynthetic and those whose structure is modified by the addition of other chemicals to the growing medium are called semi-synthetic.
An antibiotic may be tested by inoculating micro-organisms into a liquid culture medium which contains varying dilutions of the drug. Antibiotics are not effective against all micro-organisms; some are effective against bacteria, others against fungi, some against many bacteria or fungi and some against only a few. The number of types of bacteria or fungi against which a particular antibiotic is effective is called its antibacterial (or antifungal) spectrum. If it is active against many types it is called a broad-spectrum antibiotic.
Bacteria may become resistant to an antibiotic (even when it is used correctly) by several very complex mechanisms, and generally if resistance develops to one antibiotic from a group of antibiotics then there is cross-resistance to other antibiotics in that group. The use of two or more antibiotics together may help to prevent or delay the development of resistance. This is a technique frequently used in the treatment of tuberculosis but not normally recommended in treating other disorders except where two drugs act synergistically. Drug resistance may also be developed by micro-organisms because of improper treatment. This may be due to giving inappropriate doses, inappropriate intervals between doses, inadequate lengths of treatment or inappropriate antibiotic combinations.
Delay in starting antibiotics may affect response and so will the response of the body to the infecting micro-organism and to the drug. For example, pus cells may destroy the antibiotic effects, the acidity of the urine may change the effectiveness of certain antibiotics given to treat urinary infections, an abscess with tough walls will prevent antibiotics from getting into the abscess, and antibiotics may not be able to pass certain barriers (e.g. into the eye). Some may not be absorbed from the intestine and have to be given by injection.
*Also see Centoxin in A–Z of Medicines.
Patient (host) factors such as age, genetic characteristics, general physical condition (e.g. liver and kidney function), pregnancy, history of allergy to drugs and the presence of other infections may also affect the choice of an antibiotic drug. Furthermore, the patient’s response to treatment and in particular his ‘defence mechanisms’ against infections are very important.
Antibiotics may be used effectively to prevent the development of an infection if given just after exposure (e.g. high doses of penicillin after running the risk of getting gonorrhoea (providing tests have excluded syphilis)) or if given to prevent recurrence of infection with a particular organism (e.g. to prevent certain types of tonsillitis).
Adverse effects produced by antibiotics are on the increase. This is related to the increasing number of preparations available and the increasing number of patients being treated. Antibiotics may produce specific adverse effects (e.g. chloramphenicol may damage the bone marrow, neomycin may damage the kidneys), but in addition all antibiotics share two major adverse effects – the risk of allergic reactions and the risk of super-added infections with other micro-organisms.
Allergic reactions include anaphylactic shock, skin rashes, angioedema, fever and painful joints, bone-marrow damage and jaundice. Superinfections occur because many micro-organisms live together in a balanced community in many parts of our bodies (nose, mouth, intestine, skin, lungs, bladder, vagina). Any disturbance in this balance (i.e. an antibiotic, which may knock out one group of organisms) may lead to an overgrowth (superinfection) of other micro-organisms, for example, yeasts, fungi, and bacteria. These are usually minor but may occasionally be very serious and, rarely, fatal. They are difficult to treat and are more likely to occur with broad-spectrum antibiotics, in children under three years of age, in elderly and/or debilitated patients and in patients with disorders such as diabetes.
Remember – antibiotics are valuable drugs if used appropriately but because they are very effective in treating some infections they should not be used to treat just any infections (e.g. virus sore throats). They should not be used for minor infections. They should be used in appropriate doses at appropriate intervals and for an appropriate length of time. They should not be used just because they are new, particularly when effective established alternatives are available. Finally, they should never be taken without medical supervision. Never take antibiotics because ‘there were a few left in the house’, or because ‘they did my neighbour good’. Unless you and your doctor have decided that treatment with an antibiotic is appropriate for you, do not take them without advice and do not always expect them from your doctor.
Penicillin was the first antibiotic to be produced by growing penicillium mould on broth. It became available for use in 1941. The original crude extracts of the fermentation of the mould contained several penicillins. By adding various chemicals to the fermentation, a number of naturally produced penicillins have been developed; for example, benzylpenicillin (penicillin G) and phenoxymethylpenicillin (penicillin V). In addition, the chemical structure of the penicillin may be altered to produce what are called semi-synthetic penicillins. They are not wholly synthetic; the basic penicillin structure is still obtained from moulds by fermentation.
Penicillins damage the developing cell walls of multiplying bacteria, making them burst. Therefore, they kill bacteria (bactericidal ) but only when they are multiplying. Bacteria may become resistant to the effects of penicillins in two ways. They may produce enzymes which inactivate the penicillin – the best-known of these is called penicillinase, which disrupts the chemical structure (the beta-lactam ring) of the penicillin nucleus, making it inactive. Penicillinase may be referred to as a beta-lactamase *.
Some bacteria develop a tolerance to penicillin (resistance) and they just go on multiplying in the presence of doses which would previously have killed them. Development of resistance has often been related to the indiscriminate use of penicillins and it is a serious risk, particularly in surgical wards in hospital.
Allergic reactions to penicillins may occasionally occur, producing skin rashes, angioedema, fever and swollen joints. Anaphylactic shock (see p. 69), which is very rare, may be followed by death. It is more common after injections and in patients who have previously had an allergic reaction to penicillin. Penicillin allergy may be produced by skin ointments, ear drops, eye drops and throat lozenges. It may also follow the handling of penicillin (for instance in nurses drawing up injections), breathing it in and drinking milk from cows treated with penicillin for mastitis. For these reasons penicillin should not be used in topical applications and throat lozenges. The latter may produce a sore tongue, mouth and lips and also a black furring of the tongue.
Ampicillin and related penicillins may produce a skin rash in patients suffering from glandular fever or chronic lymphatic leukaemia. This is different from the usual penicillin rash. It is probably a toxic reaction and penicillins can be used in future in these patients. All penicillins may occasionally cause diarrhoea, nausea, heartburn and itching of the anus.
Apart from allergy, penicillins are very safe drugs. Adverse effects are more likely to occur because of errors in prescribing than from any other cause. Remember, cross-allergy to penicillin occurs: if you are allergic to one (say, penicillin V) you may be allergic to another (e.g. ampicillin). Skin-testing for a rare adverse effect of the penicillins is irritation of the brain, producing disorders of brain function (encephalopathy). This occurs when very high doses are used intravenously or intramuscularly, particularly in patients with impaired kidney function. Injection of penicillin into the spinal fluid in high doses can cause convulsions and should be avoided.
*Note: Penicillins and cephalosporins are referred to as beta-lactam antibiotics because they have a beta-lactam ring as part of their basic chemical structure.
Penicillins should not be taken for trivial infections or by patients who have had a previous allergic reaction. They should be taken with caution by patients who have had an allergic reaction to any other drug. They provide us with a range of very valuable antibiotics, which, if used appropriately, are very effective.
Penicillins are classified as follows:
- benzylpenicillin (penicillin G, Crystapen)
- phenoxymethylpenicillin (penicillin V, Apsin, Tenkicin)
- flucloxacillin (Floxapen, Fluclomix, Galfoxin, Ladropen, Zoxin)
- amoxicillin (Almodan, Amix, Amoram, Amoxil, Galenamox, Rimoxallin)
- ampicillin (Penbritin, Rimacillin)
These are effective against severe infections caused by pseudomonas bacteria which are not affected by other penicillins.
- piperacillin (Pipril, in Tazocin)
- Co-amoxiclav (Augmentin, Augmentin Duo) contains amoxycillin with a beta-lactamase inhibitor (clavulanic acid ) which inhibits penicillinase. Timentin contains ticarcillin and clavulanic acid. Preparations containing a broad-spectrum penicillin and a penicillinase-resistant penicillin include co-fluampicil (Magnapen) which contains ampicillin and flucloxacillin. Tazocin contains piperacillin and the beta-lactamase inhibitor tazobactam.
- Pivmecillinam (Selexid) is hydrolysed in the body to mecillinam, which is the active drug. It is used in bacterial infections of the urinary tract.
Cephalosporins and Cephamycins
The cephalosporins are broad-spectrum semi-synthetic antibiotics produced from a natural mould antibiotic (cephalosporin C). They act on much the same groups of bacteria as the natural penicillins. They also act on a broad spectrum of bacteria in the same way as ampicillin and are effective against some bacteria which are resistant to ampicillin. They may produce allergic reactions, and cross-allergy may occur between cephalosporins and some penicillins in some patients. About 10 per cent of patients allergic to penicillin will be allergic to cephalosporins. Cross-resistance may be shown to cephalosporins by bacteria resistant to methicillin and cloxacillin.
The cephalosporin group includes cefaclor (Distaclor), cefadroxil (Baxan), cefalexin (Ceporex, Keflex), cefamandole(cephamandole) (Kefadol), cefradine(cephradine) (Velosef), cefazolin (Kefzol), cefixime (Suprax), cefotaxime (Claforan), cefoxitin (Mefoxin), cefpirome (Cefrom), cefpodoxime (Orelox), cefprozil (Cefzil), ceftazidime (Fortum, Kefadim), ceftriaxone (Rocephin), and cefuroxime (Zinacef, Zinnat).
Other similar antibiotics include aztreonam (Azactam) and meropenem (Meronem) which have a wide spectrum of activity against bacteria, including beta-lactamase producing bacteria and imipenem which is combined with cilastatin in Primaxin. It has a broad spectrum of activity. The cilastatin blocks an enzyme in the kidneys which inactivates imipenem.
This group includes erythromycin (Arpimycin, Erycen, Erymax, Erythrocin, Erythroped, Ilosone, Rommix, Tiloryth), azithromycin (Zithromax) and clarithromycin (Klaricid ).
Erythromycin is active against a narrow group of bacteria similar to those sensitive to the natural penicillins. It is bacteriostatic. It may be of use in treating tissue infections caused by bacteria resistant to the natural penicillins or if the patient is allergic to penicillins. It has been widely used but bacteria quickly become resistant to it, especially if it is given for more than one week. Its use has been replaced by other antibiotics in many cases. It is inactivated by the acid in the stomach and has to be given in acid-resistant capsules, or specially covered tablets (enteric-coated) as one of its esters (e.g. erythromycin oleate or stearate). Erythromycin may cause liver damage with jaundice and fever if a second or subsequent course is given, particularly if it is given for more than two weeks. This is thought to be an allergic reaction and clears up when the drug is stopped.
Azithromycin and clarithromycin are not as easily destroyed by the acid in the stomach and can be given in much lower doses. They cause fewer stomach and bowel upsets than erythromycin.
This group includes clindamycin (Dalacin C). It may cause severe diarrhoea, and also a potentially life-threatening inflammation of the bowel (pseudomembranous colitis) which occurs more commonly in middle-aged and elderly women, especially following surgery. While this occurs, rarely, with other antibiotics as well, the incidence appears higher with clindamycin and its use should be restricted to the limited number of infections where it is clearly the drug of choice.
The first tetracycline to be discovered was Aureomycin, in 1948; it was grown from moulds. Another one, called Terramycin, was discovered in 1950. Two years later their chemical structure was determined and it was found to consist of a basic structure of four rings (tetra-cyclic). Therefore, the antibiotics were called tetracyclines and the generic name of chlortetracycline was given to Aureomycin and oxytetracycline to Terramycin. The names Aureomycin and Terramycin remained as brand names. Oxytetracycline (Terramycin) is also available under other brand names: Oxymycin and Oxytetramix. Since the fifties numerous tetracyclines have been produced and tested but only a few have proved to be of value. These include demeclocycline (Ledermycin), doxycycline (Vibramycin), lymecycline (Tetralysal), minocycline (Minocin) and tetracycline (Achromycin, in Deteclo, Economycin).
One of the problems with the tetracyclines is that they are only partially absorbed from the intestine and enough reaches the lower bowel to affect the normal organisms which live there. This may alter the balance between bacteria and fungi and lead to a superinfection with thrush (Candida), which can infect the mouth, bowel, anus and vulva, producing soreness and irritation. A more serious risk is a super-added infection with resistant bacteria which may cause severe enteritis and, very rarely, death. This is more likely to follow the use of tetracycline during abdominal operations. These super-added infections may also affect the lungs. Demeclocycline, doxycycline and minocycline are better absorbed than the other tetracyclines and the risk of enteritis is reduced.
Absorption of tetracyclines from the intestine may be decreased by interaction with calcium (e.g. in milk), iron and magnesium salts (e.g. in antacids) when these are taken at the same time. None of these should be taken at the same time as a tetracycline or its absorption will be decreased and the desired therapeutic effects will not be achieved. Absorption is similarly reduced by food, with the exception of doxycycline and minocycline. Tetracyclines are excreted in the urine and in the bile. Doxycycline is excreted primarily via the bile and hence is the safest tetracycline in kidney failure. Since its excretory products are largely inactive, it has less effect on natural bowel bacteria than other tetracyclines, and accordingly a lower incidence of superinfection.
Very rarely, tetracyclines given by injection may produce severe liver damage (sometimes fatal) when given to pregnant women with infections of their kidneys. Tetracyclines are deposited in growing teeth, producing discoloration and staining in young children. It is not only the first set of teeth which is affected – the adult teeth may also be stained for life and there is an added risk of tooth decay. They are also deposited in bone and bone growth stops during tetracycline treatment. These effects on teeth and bone may occur before the baby is born (if the mother is given tetracyclines) and right on into childhood. Therefore, they should be avoided in pregnancy and preferably not given to children under twelve years of age. They may discolour nails at any age if taken over a prolonged period. Doxycycline is said to cause less staining than the other tetracyclines. Allergic reactions to tetracycline drugs are rare. Sensitivity of the skin to sunlight may occur in patients receiving demeclocycline or doxycycline; this is less likely with the others.
Tetracyclines (other than doxycycline and minocycline) may affect protein production in the body and also kidney function. These may be indicated by a rise in the blood levels of breakdown products of proteins (as estimated by blood urea levels, for example). Urea and other waste products are excreted by the kidneys and this may have no consequence if the kidneys are healthy. However, if their function is impaired these waste products may rise in the blood, producing loss of appetite, vomiting and weakness. This is called kidney failure and may occur unexpectedly in elderly patients who are given tetracyclines, usually for a chest infection.
Streptomycin and Other Aminoglycosides
Streptomycin was discovered in soil in 1944. Other aminoglycoside antibiotics have since been discovered. They include amikacin (Amikin), framycetin (Soframycin), gentamicin (Cidomycin, Genticin), kanamycin (Kannasyn), neomycin (Nivemycin), netilmicin (Netillin), tobramycin (Nebcin). They are bactericidal against a wide spectrum of bacteria responsible for serious infections. Bacteria quickly develop resistance to streptomycin and less quickly to the others.
They are poorly absorbed from the intestine and have to be given by intra-muscular or intravenous injection. They are quickly excreted by the kidneys and impaired kidney function may lead to dangerously high blood levels. They are painful when given by injection and their principal adverse effects include deafness (which may be permanent) and disorders of the organ of balance due to damage to the main nerve which supplies the ear and organ of balance. They may also damage the kidneys and affect nerve-muscle junctions, producing muscle weakness and depression of respiration.
These adverse effects are more likely to occur with high doses, prolonged courses of treatment, in patients over middle-age and in patients with impaired kidney function. Allergic reactions may occur, particularly with streptomycin, which may also cause severe allergic skin reactions in those handling the drug (e.g. nurses). Anyone handling the drug should be very cautious and wear gloves. They should not be used in pregnancy since they can damage the baby’s hearing. Their use along with certain diuretics which can damage hearing (e.g. frusemide, ethacrynic acid) should be avoided and their use should always be monitored using blood level measurements.
Streptomycin is principally used to treat tuberculosis in combination with other drugs such as isoniazid. Neomycin is too toxic for systematic use. It is not absorbed from the intestine and can be used to sterilize the bowel before surgery. Its main use is in applications for the skin, eyes and ears. Patients can become hypersensitive to neomycin.
Framycetin is similar to neomycin; only used in topical applications. Gentamicin is related to neomycin; it is active against a wide spectrum of bacteria. It is used to treat severe infections. Tobramycin has similar actions to gentamicin. Amikacin is useful against bacteria resistant to gentamicin. Kanamycin is rarely used except in serious infections resistant to gentamicin.
Polymyxins and Related Antibiotics
The polymyxins are a group of antibiotics which include colistimethate (Colomycin). It is used in topical applications and by injection to treat very severe infections and by mouth to sterilize the bowel before bowel surgery. Polymyxins are poorly absorbed from the intestine and even with injections it is difficult to get a high blood level; therefore large doses have to be used. They may produce kidney damage and, rarely, damage to nerve-muscle junctions, producing muscle weakness and depression of respiration. Polymyxin B (in Gregoderm, in Maxitrol, in Neosporin, in Otosporin, in Polyfax, in Polytrim) is used externally.
Some Other Antibacterial Drugs
Chloramphenicol (Chloromycetin, Kemicetine) was the first broad-spectrum antibiotic to be discovered. It was introduced in 1947 and soon became widely promoted and prescribed. However, it may occasionally knock out red and white cell production by the bone marrow and its use is now restricted to treating typhoid fever and a certain type of meningitis. It is also used in eye and ear applications.
Sodium fusidate (Fucidin) is the sodium salt of fusidic acid. It is well absorbed from the intestine, broken down in the liver and excreted in the urine and bile. It is active against penicillinase-producing staphylococci and should be reserved specifically for treating these infections. It penetrates bone and is used to treat bone infection (osteomyelitis). Bacteria readily develop resistance. It may be given in combination with other antibiotics such as flucloxacillin.
The rifamycins are related to streptomycin. Several have been produced and one of them, rifampicin (Rifadin, Rimactane), is used to prevent meningococcal meningitis in contacts and to treat tuberculosis, and leprosy.
Vancomycin (Vancocin) is a glycopeptide that is too toxic for routine use and should be reserved for treating infections resistant to other antibiotics or patients with colitis caused by other antibiotics. It is not absorbed from the intestine and has to be given by intravenous injections, which may be painful and produce thrombophlebitis. When given to treat pseudo-membranous colitis (a severe type of colitis produced by antibiotics) it is given by mouth, and because it is not absorbed it does not produce systemic effects. Teicoplanin (Targocid ) is similar to vancomycin but has a long duration of action. It can be given by injection into a muscle as well as into a vein.
Synercid contains a combination of the streptograms quinupristin and dalfopristin. It is effective in Gram-positive bacterial infections. It is reserved for treating infections where other antibacterials have failed, e.g. methicillin resistant slaphylococcus aureus (MRSA infections).
4-Quinolones are effective antibacterial drugs. Nalidixic acid (Mictral, Negram, Uriben), cinoxacin (Cinobac) and norfloxacin (Utinor) are used to treat infections of the urinary tract. Ciprofloxacin (Ciproxin) and levofloxacin (Tavanic) are active against a wide range of organisms and are useful for treating bacterial diarrhoea infections, certain lung infections, gonorrhoea, urinary tract infections and certain blood poisonings (septicaemia). Ofloxacin (Tarivid ) is a synthetic drug related to nalidixic acid. It is used to treat infections of the urinary tract and genital tract and chest infections.
Metronidazole (Flagyl, Metrolyl, Vaginyl) and tinidazole (Fasigyn) are active against anaerobic bacteria and protozoa. They are of particular use in preventing and treating abdominal surgical infections and in treating infections of the vagina or mouth (acute ulcerative gingivitis). They are also used to treat amoebiasis and giardiasis.
In 1935 it was found that the red dye, prontosil rubra, protected mice from streptococcal infections and that the active antibacterial agent in the body was a breakdown product of the red dye called sulphanilamide. Following this discovery hundreds of similar drugs have been produced and tested for antibacterial activity. They belong to the sulphonamide group and they stop bacteria from multiplying (bacteriostatic) by affecting (competing with) the use of a vitamin called folic acid, which is essential for their growth.
These drugs were used extensively in the past but because of increasing bacterial resistance and the availability of other more effective and less toxic antibiotics their use has significantly decreased. One use is in the treatment of urinary tract infections caused by bacteria sensitive to the sulphonamides.
Adverse effects to sulphonamide drugs are relatively common and vary according to the particular sulphonamide used and the susceptibility of the patient. Those patients who break down certain drugs slowly (slow acetylators) may be more at risk.
The sulphonamides in use include:
- sulfametopyrazine (Kelfizine W)
Those sulphonamides that are poorly absorbed from the intestine (calcium sulphaloxate and sulphaguanidine) were previously used to treat infections of the intestine and to prepare the bowel before abdominal surgery. They should not be used for these purposes. Silver sulfadiazine (Flamazine) is used to treat infected skin burns, leg ulcers and bed sores.
Combinations of Sulphonamides with Trimethoprim (Co-trimoxazole)
Trimethoprim (Monotrim, Trimopan) blocks the use of folic acid by bacteria just after the stage blocked by sulphonamides. It is effective on its own in treating urinary tract infections and some chest infections. However, it is often given with a sulphonamide, when both drugs block folic acid. This is an example of one drug potentiating the action of another by acting synergistically. While sulphonamides alone are bacteriostatic this combination is bactericidal. Co-trimoxazole (Chemotrim, Comixco, Fectrim, Septrin) contains the sulphonamide sulfamethoxazole and trimethoprim. Trimethoprim is well absorbed when taken by mouth and sulfamethoxazole was selected because it is absorbed and excreted at a similar rate to trimethoprim, so that after a few days the ratio of the two drugs in the blood-stream and urine is kept relatively constant to produce optimal synergism (i.e. working together).
Co-trimoxazole may produce any of the adverse effects of sulphonamides and of trimethoprim. Since it contains two drugs, bacterial sensitivity to each drug should be tested and it should only be used if the bacteria are sensitive to both drugs, when it obviously has a wider spectrum of activity than sulphonamides alone.
Warning: Co-trimoxazole has been over-used with the result that some patients (particularly elderly ones) have suffered severe adverse effects e.g. blood disorders and generalized skin disorders. Its use should be limited to treating a type of pneumonia that occurs in AIDS patients (pneumocystis carinii pneumonia: PCP), toxoplasmosis and nocardiasis. It should only be used to treat flame-ups of chronic bronchitis or urinary infections when the infecting organisms have been shown to be sensitive to both drugs in co-trimoxazole. Also, it should not be used to treat acute otitis media in children unless there is some very good reason for doing so.