On a few occasions it is appropriate to use antibacterial drugs prophylactically. Wherever possible a suitably specific narrow- spectrum drug should be used.
ANTIBIOTIC PROPHYLAXIS OF INFECTIVE ENDOCARDITIS
An important recent change is that fewer patients are deemed to require antibiotic prophylaxis against infective endocarditis;
it should be restricted to patients who have previously had
endocarditis, cardiac valve replacement surgery (mechanical or biological prosthetic valves), or surgically constructed systemic or pulmonary shunts or conduits. In such patients, all dental procedures involving dento-gingival manipulation will require antibiotic prophylaxis, as will certain genito-urinary, gastro- intestinal, respiratory or obstetric/gynaecological procedures.
Intravenous antibiotics are no longer recommended unless the patient cannot take oral antibiotics. The latest guidelines (2006) by the Working Party of the British Society for Antimicrobial Chemotherapy can be found at http://jac.oxfordjournals.org/
cgi/reprint/dkl121v1. These are updated periodically.
For dental procedures, in addition to prophylactic anti- biotics, the use of chlorhexidine0.2% mouthwash five minutes before the procedure may be a useful supplementary measure.
PROPHYLACTIC PREOPERATIVE ANTIBIOTICS GENERAL PRINCIPLES
1. Prophylaxis should be restricted to cases where the procedure commonly leads to infection, or where infection, although rare, would have devastating results.
2. The antimicrobial agent should preferably be bactericidal and directed against the likely pathogen.
3. The aim is to provide high plasma and tissue concentrations of an appropriate drug at the time of bacterial
contamination. Intramuscular injections can usually be given with the premedication or intravenous injections at the time of induction. Drug administration should seldom exceed 48 hours. Many problems in this area arise because of failure to discontinue ‘prophylactic’ antibiotics, a mistake that is easily made by a busy junior house-surgeon who does not want to take responsibility for changing a prescription for a patient who is apparently doing well post-operatively. Local hospital drug and therapeutics committees can help considerably by instituting sensible guidelines on the duration of prophylactic antibiotics.
4. If continued administration is necessary, change to oral therapy post-operatively wherever possible.
The British National Formulary provides a good summary of the use of antibacterial drugs preoperatively, which may be varied according to local guidelines based on regional pat- terns of bacterial susceptibility/resistance.
COMMONLY PRESCRIBED ANTIBACTERIAL DRUGS
β-LACTAM ANTIBIOTICS
These drugs each contain a β-lactam ring. This can be broken down by β-lactamase enzymes produced by bacteria, notably by many strains of Staphylococcus andHaemophilus influenzae, which are thereby resistant. β-Lactam antibiotics kill bacteria by inhibiting bacterial cell wall synthesis. Penicillins are excreted in the urine. Probenecid blocks the renal tubular secretion
COMMONLYPRESCRIBEDANTIBACTERIALDRUGS 325
ofpenicillin. This interaction may be used therapeutically to produce higher and more prolonged blood concentrations of penicillin. Antibiotics in this group include the penicillins, monobactams, carbapenems and cephalosporins.
PENICILLINS Use
Benzylpenicillin(penicillin G) is the drug of choice for strep- tococcal, pneumococcal, gonococcal and meningococcal infec- tions, and is also useful for treatment of anthrax, diphtheria, gas gangrene, leptospirosis, syphilis, tetanus, yaws and Lyme disease in children.
Adverse effects
The adverse effects include:
1. anaphylaxis (in approximately 1 in 100 000 injections);
2. rashes (3–5% of patients) can, rarely, be severe (e.g.
Stevens–Johnson syndrome – see Chapter 12);
3. serum sickness – type III hypersensitivity;
4. other idiosyncratic reactions including haemolytic anaemia and thrombocytopenia;
5. in renal failure, high-dose penicillincauses encephalopathy and seizures.
Limitations of benzylpenicillininclude:
1. It is acid labile and so must be given parenterally (inactivated in gastric acid).
2. It has a short half-life, so frequent injections are required.
3. Development of resistant β-lactamase-producing strains can occur.
4. It has a narrow antibacterial spectrum.
Two preparations with similar antibacterial spectra are used to overcome the problems of acid lability/frequent injection:
1. Procaine benzylpenicillin– this complex releases penicillinslowly from an intramuscular site, so a twice daily dosage only is required.
2. Phenoxymethylpenicillin(‘penicillin V’) – this is acid stable and so is effective when given orally (40–60%
absorption). Although it is useful for mild infections, blood concentrations are variable, so it is not used in serious infections or with poorly sensitive bacteria.
Tablets are given on an empty stomach to improve absorption.
β-LACTAMASE-RESISTANT PENICILLIN
Flucloxacillinwas developed to overcome β-lactamase-produc- ing strains. Otherwise, it has a similar antibacterial spectrum to benzylpenicillin. It is effective against β-lactamase-producing organisms. It is used for the treatment of staphylococcal infec- tions (90% of hospital staphylococci are resistant to benzylpeni- cillinand 5–10% are resistant to flucloxacillin).
EXTENDED-RANGE PENICILLINS AMPICILLIN/AMOXICILLIN Uses
In addition to streptococcal (including pneumococcal) strains, ampicillin and amoxicillin are also effective against many strains of Haemophilus influenzae,E. coli,Streptococcus faecalisand Salmonella. They are used for a variety of chest infections (e.g.
bronchitis, pneumonia), otitis media, urinary tract infections, biliary infections and the prevention of bacterial endocarditis (amoxicillin). Amoxicillin is somewhat more potent than ampicillin, penetrates tissues better and is given three rather than four times daily. Both are susceptible to β-lactamases.
Adverse effects
Rashes are common and may appear after dosing has stopped.
There is an especially high incidence in patients with infec- tious mononucleosis or lymphatic leukaemia.
Pharmacokinetics
The half-life of each drug is about 1.5 hours and they are pre- dominantly renally excreted.
CO-AMOXICLAV
Co-amoxiclavis a combination of amoxicillinandclavulanic acid, a β-lactamase inhibitor. In addition to those bacteria that are susceptible to amoxicillin, most Staphylococcus aureus, 50% of E. coli, some Haemophilus influenzaestrains and many Bacteroides andKlebsiellaspecies are susceptible to co-amoxiclav. Adverse effects are similar to those of amoxicillin, but abdominal dis- comfort is more common.
ANTIPSEUDOMONAL PENICILLINS
Standard penicillins are not effective against Pseudomonas. This is not usually a problem, as these organisms seldom cause dis- ease in otherwise healthy people. However, Pseudomonasinfec- tion is important in neutropenic patients (e.g. those undergoing cancer chemotherapy) and in patients with cystic fibrosis.
Penicillins with activity against Pseudomonashave been devel- oped and are particularly useful in these circumstances. These includepiperacillin,azlocillinandticarcillin.
Uses
These expensive intravenous penicillins are not used routinely.
Their efficacy against Gram-positive organisms is variable and poor. They are useful against Gram-negative infections, partic- ularly with Pseudomonasand they are also effective against many anaerobes. These drugs have a synergistic effect when combined with aminoglycosides in Pseudomonassepticaemias.
Combinations of ticarcillinor of piperacillinwithβ-lactamase inhibitors designed to overcome the problem of β-lactamase formation by Pseudomonasare commercially available.
Adverse effects
These drugs predispose to superinfection. Rashes, sodium over- load, thrombocytopenia and platelet dysfunction can occur.
326 ANTIBACTERIAL DRUGS
Pharmacokinetics
Absorption of these drugs from the gut is inadequate in the life-threatening infections for which they are mainly indicated.
They are given intravenously every 4–6 hours. Their half-lives range from 1 to 1.5 hours and they are renally excreted.
CEPHALOSPORINS
FIRST-GENERATION CEPHALOSPORINS
So-called first-generation cephalosporins (e.g. cephalexin, cefaclor, cefadroxil) are effective against Streptococcus pyo- genesandStreptococcus pneumoniae,E. coliand some staphylo- cocci. They have few absolute (i.e. uniquely advantageous) indications. Their pharmacology is similar to that of the peni- cillins and they are principally renally eliminated.
SECOND- AND THIRD-GENERATION CEPHALOSPORINS
Second- and third-generation cephalosporins are active againstH. influenzaeand in some instances Pseudomonasand anaerobes, at the expense of reduced efficacy against Gram- positive organisms. β-Lactamase stability has been increased.
Arguably the most generally useful member of the group is cefuroxime, which combines lactamase stability with activity against streptococci, staphylococci, H. influenzaeandE. coli. It is given by injection eight-hourly (an oral preparation is also available, as cefuroxime axetil). It is expensive, although when used against Gram-negative organisms that would other- wise necessitate use of an aminoglycoside, this cost is partly offset by savings from the lack of need for plasma concentra- tion determinations.
Of the third-generation cephalosporins, ceftazidime, cef- triaxoneandcefotaximeare useful in severe sepsis, especially because (unlike earlier cephalosporins) they penetrate the blood–brain barrier well and are effective in meningitis.
Adverse effects
About 10% of patients who are allergic to penicillins are also allergic to cephalosporins. Some first-generation cephalosporins are nephrotoxic, particularly if used with furosemide, amino- glycosides or other nephrotoxic agents. Some of the third- generation drugs are associated with bleeding due to increased prothrombin times, which is reversible with vitamin K.
MONOBACTAMS
Monobactams (e.g. aztreonam) contain a 5-monobactam ring and are resistant to β-lactamase degradation.
AZTREONAM Uses
Aztreonamis primarily active against aerobic Gram-negative organisms and is an alternative to an aminoglycoside. It is used
in severe sepsis, often hospital acquired, especially infections of the respiratory, urinary, biliary, gastro-intestinal and female genital tracts. It has a narrow spectrum of activity and cannot be used alone unless the organism’s sensitivity to aztreonam is known.
Mechanism of action
The 5-monobactam ring binds to bacterial wall transpepti- dases and inhibits bacterial cell wall synthesis in a similar way to the penicillins.
Adverse effects
Rashes occur, but there appears to be no cross-allergenicity with penicillins.
Pharmacokinetics
Aztreonamis poorly absorbed after oral administration, so it is given parenterally. It is widely distributed to all body com- partments, including the cerebrospinal fluid. Excretion is renal and the usual half-life (one to two hours) is increased in renal failure.
IMIPENEM–CILASTATIN AND MEROPENEM Uses
Imipenem, a carbapenem, is combined with cilastatin, which is an inhibitor of the enzyme dehydropeptidase I found in the brush border of the proximal renal tubule. This enzyme breaks downimipenemin the kidney. Imipenemhas a very broad spectrum of activity against Gram-positive, Gram-negative and anaerobic organisms. It is β-lactamase stable and is used for treat- ing severe infections of the lung and abdomen, and in patients with septicaemia, where the source of the organism is unknown.
Meropenemis similar to imipenem, but is stable to renal dehy- dropeptidase I and therefore can be given without cilastatin.
Adverse effects
Imipenemis generally well tolerated, but seizures, myoclonus, confusion, nausea and vomiting, hypersensitivity, positive Coombs’ test, taste disturbances and thrombophlebitis have all been reported. Meropenemhas less seizure-inducing potential and can be used to treat central nervous system infection.
Pharmacokinetics
Imipenemis filtered and metabolized in the kidney by dehy- dropeptidase I. This is inhibited by cilastatinin the combina- tion.Imipenemis given intravenously as an infusion in three or four divided daily doses.
AMINOGLYCOSIDES Uses
Aminoglycosides are highly polar, sugar-containing deriva- tives. They are powerful bactericidal agents that are active against many Gram-negative organisms and some Gram- positive organisms, with activity against staphylococci and COMMONLYPRESCRIBEDANTIBACTERIALDRUGS 327
Enterococcus faecalis, but not (when used alone) against other streptococci. They synergize with penicillins in killing Streptococcus faecalisin endocarditis. Aminoglycosides are used in serious infections including septicaemia, sometimes alone but usually in combination with other antibiotics (penicillins or cephalosporins). Gentamicin is widely used and has a broad spectrum, but is ineffective against anaerobes, many streptococci and pneumococci.
Tobramycinis probably somewhat less nephrotoxic than gentamicin.Amikacinis more effective than gentamicinfor pseudomonal infections and is occasionally effective against organisms resistant to gentamicin. It is principally indicated in serious infections caused by Gram-negative bacilli that are resistant to gentamicin. Topical gentamicin or tobramycin eye drops are used to treat eye infections.
Mechanism of action
These drugs are transported into cells and block bacterial pro- tein synthesis by binding to the 30S ribosome.
Adverse effects
These are important and are related to duration of therapy and trough plasma concentrations. They are more frequent in the elderly and in renal impairment. Therapeutic monitoring is performed by measuring plasma concentrations before dosing (trough) and at ‘peak’ levels (usually at an arbitrary one hour after dosing). Eighth nerve damage is potentially catastrophic and is often irreversible. Acute tubular necrosis and renal fail- ure are usually reversible if diagnosed promptly and the drug stopped or the dose reduced. Hypersensitivity rashes are uncommon. Bone marrow suppression is rare. Exacerbation of myasthenia gravis is predictable in patients with this disease.
Pharmacokinetics
Aminoglycosides are poorly absorbed from the gut and are given by intramuscular or intravenous injection. They are poorly protein bound (30%) and are excreted renally. The half- life is short, usually two hours, but once daily administration is usually adequate. This presumably reflects a post-antibiotic effect whereby bacterial growth is inhibited following clear- ance of the drug. In patients with renal dysfunction, dose reduction and/or an increased dose interval is required.
Cerebrospinal fluid (CSF) penetration is poor.
Drug interactions
Aminoglycosides enhance neuromuscular blockade of non- depolarizing neuromuscular antagonists. Loop diuretics potentiate their nephrotoxicity and ototoxicity.
CHLORAMPHENICOL Uses
Chloramphenicolhas a broad spectrum of activity and pene- trates tissues exceptionally well. It is bacteriostatic, but is extremely effective against streptococci, staphylococci, H. influenzae, salmonellae and others. Uncommonly it causes
aplastic anaemia, so its use is largely confined to life-threatening disease (e.g. H. influenzaeepiglottitis, meningitis, typhoid fever) and to topical use as eyedrops.
Mechanism of action
Chloramphenicol inhibits bacterial ribosome function by inhibiting the 50S ribosomal peptidyl transferase, thereby pre- venting peptide elongation.
Adverse effects These include:
1. haematological effects– dose-related erythroid suppression is common and predictable, but in addition aplastic anaemia occurs unpredictably with an incidence of approximately 1:40 000. This is irreversible in 50% of cases.
It is rarely, if ever, related to the use of eyedrops.
2. grey baby syndrome– the grey colour is due to shock (hypotension and tissue hypoperfusion).
Chloramphenicolaccumulates in neonates (especially if premature) due to reduced glucuronidation in the immature liver (see Chapter 10).
3. other– sore mouth, diarrhoea, encephalopathy and optic neuritis.
Pharmacokinetics
Chloramphenicolis well absorbed following oral administra- tion and can also be given by the intramuscular and intra- venous routes. It is widely distributed and CSF penetration is excellent. It mainly undergoes hepatic glucuronidation, but in neonates this is impaired.
Drug interactions
Chloramphenicol inhibits the metabolism of warfarin, phenytoinandtheophylline.
MACROLIDES
Macrolide antibiotics (e.g. erythromycin, clarithromycin, azithromycin) have an antibacterial spectrum similar, but not identical to that of penicillin. Distinctively, they are effective against several unusual organisms, including Chlamydia, LegionellaandMycoplasma.
ERYTHROMYCIN Uses
Uses include respiratory infections (including Mycoplasma pneumoniae, psittacosis and Legionnaires’ disease), whooping cough, Campylobacter enteritis and non-specific urethritis.
Erythromycinis a useful alternative to penicillinin penicillin- allergic patients (except meningitis: it does not penetrate the CSF adequately). It is useful for skin infections, such as low- grade cellulitis and infected acne, and is acceptable for patients with an infective exacerbation of chronic bronchitis. It is most commonly administered by mouth four times daily, although when necessary it may be given by intravenous infusion.
328 ANTIBACTERIAL DRUGS
Mechanism of action
Macrolides bind to bacterial 50S ribosomes and inhibit protein synthesis.
Pharmacokinetics
Well absorbed orally and distributed adequately to most sites except the brain, macrolides are inactivated by hepatic N-demethylation,15% being eliminated unchanged in the urine. Food delays absorption but may reduce gastro-intestinal side effects.
Adverse effects
Erythromycinis remarkably safe and may be used in pregnancy and in children. Nausea, vomiting, diarrhoea and abdominal cramps are the most common adverse effects reported, related to direct pharmacological actions rather than allergy. Cholestatic jaundice has been reported following prolonged use.
Intravenous administration frequently causes local pain and phlebitis.
Drug interactions
Erythromycininhibits cytochrome P450 and causes accumu- lation of theophylline, warfarin and terfenadine. This can result in clinically important adverse effects.
AZITHROMYCIN AND CLARITHROMYCIN
Each of these has greater activity than erythromycinagainst H. influenzae. Azithromycin is less effective against Gram- positive bacteria than erythromycin, but has a wider spectrum of activity against Gram-negative organisms. Clarithromycin is an erythromycin derivative with slightly greater activity than the parent compound; tissue concentrations are higher than with erythromycin. It is given twice daily.
Azithromycinandclarithromycinare more expensive than erythromycin, but cause fewer gastro-intestinal side effects.
TETRACYCLINES Uses
Tetracyclines (e.g. tetracycline,oxytetracycline,doxycycline) have a broad range of antibacterial activity covering both Gram-positive and Gram-negative organisms and, in addition organisms such as Rickettsia,ChlamydiaandMycoplasma. They are used in atypical pneumonias and chlamydial and rick- ettsial infections, and remain useful in treating exacerbations of chronic bronchitis or community-acquired pneumonia.
They are not used routinely for staphylococcal or streptococ- cal infections because of the development of resistance.
Tetracyclines are used in the long-term treatment of acne (Chapter 51).
Mechanism of action
Tetracyclines bind to the 30S subunit of bacterial ribosomes and prevent binding of the aminoacyl-tRNA to the ribosome acceptor site, thereby inhibiting protein synthesis.
Adverse effects These include:
1. nausea, vomiting and diarrhoea (pseudomembranous colitis due to Clostridium difficilereported occasionally);
2. hypersensitivity reactions (including rash, exfoliative dermatitis, Stevens–Johnson syndrome, urticaria, angioedema, anaphylaxis, pericarditis);
3. worsening of renal failure;
4. hepatotoxicity (rare);
5. discoloration and damage of the teeth and bones of the fetus if the mother takes tetracyclines after the fifth month of pregnancy, and of children; they should therefore be avoided in pregnancy and children under 12 years.
Pharmacokinetics
Tetracyclines are well absorbed orally when fasting, but their absorption is reduced by food and antacids. They undergo elimination by both the liver and the kidney. The half-life varies between different members of the group, ranging from six to 12 hours. The shorter-acting drugs are given four times daily and the longer-acting ones once daily. Doxycycline is given once daily, can be taken with food and is not contraindi- cated in renal impairment.
Drug interactions
Tetracyclines chelate calcium and iron in the stomach, and their absorption is reduced by the presence of antacids or food.
SODIUM FUSIDATE Uses
Fusidic acidis combined with other drugs to treat staphylo- coccal infections, including penicillin-resistant strains. It pen- etrates tissues (including bone) well. It is normally used in conjunction with flucloxacillin for serious staphylococcal infections. It is also available as eyedrops for the treatment of bacterial conjunctivitis.
Mechanism of action
It inhibits bacterial protein synthesis.
Adverse effects
Adverse effects are rare, but include cholestatic jaundice.
Pharmacokinetics
When administered either orally or intravenously, its half-life is four to six hours and it is excreted primarily via the liver.
VANCOMYCIN
Uses and antibacterial spectrum
Vancomycinis valuable in the treatment of resistant infections due to Staphylococcus pyogenes. It is also rarely used to treat COMMONLYPRESCRIBEDANTIBACTERIALDRUGS 329
other infections, for example Staphylococcus epidermidisendo- carditis, and is given orally for pseudomembranous colitis caused by Clostridium difficile.
Mechanism of action
Vancomycininhibits bacterial cell wall synthesis.
Adverse effects These include:
• hearing loss;
• venous thrombosis at infusion site;
• ‘red man’ syndrome due to cytokine/histamine release following excessively rapid intravenous administration;
• hypersensitivity (rashes, etc.);
• nephrotoxicity.
Pharmacokinetics
Vancomycinis not absorbed from the gut and is usually given as an intravenous infusion (except for the treatment of pseudomembranous colitis). It is eliminated by the kidneys.
Because of its concentration-related toxicity, the dose is adjusted according to the results of plasma concentration monitoring.
TEICOPLANIN
Teicoplaninhas a longer duration of action, but is otherwise similar to vancomycin.
METRONIDAZOLE Uses
Metronidazoleis a synthetic drug with high activity against anaerobic bacteria. It is also active against several medically important protozoa and parasites (see Chapter 47). It is used to treat trichomonal infections, amoebic dysentery, giardiasis, gas gangrene, pseudomembranous colitis and various abdom- inal infections, lung abscesses and dental sepsis. It is used pro- phylactically before abdominal surgery.
Mechanism of action
Metronidazolebinds to DNA and causes strand breakage. In addition, it acts as an electron acceptor for flavoproteins and ferredoxins.
Adverse effects These include:
1. nausea and vomiting;
2. peripheral neuropathy;
3. convulsions, headaches;
4. hepatitis.
Pharmacokinetics
Metronidazoleis well absorbed after oral or rectal administra- tion, but is often administered by the relatively expensive intravenous route. The half-life is approximately six hours. It is eliminated by a combination of hepatic metabolism and renal excretion. Dose reduction is required in renal impairment.
Drug interactions
Metronidazoleinteracts with alcohol because it inhibits alde- hyde dehydrogenase and consequently causes a disulfiram- like reaction. It is a weak inhibitor of cytochrome P450.
SULPHONAMIDES AND TRIMETHOPRIM
Sulphonamides and trimethopriminhibit the production of folic acid at different sites of its synthetic pathway and are synergistic in vitro. There is now widespread resistance to sulphonamides, and they have been largely replaced by more active and less toxic antibacterial agents. The sulfamethoxazole–trimethoprim combi- nation (co-trimoxazole) is effective in urinary tract infections, prostatitis, exacerbations of chronic bronchitis and invasive Salmonella infections, but with the exception of Pneumocystis cariniiinfections (when high doses are used), trimethoprimalone is generally preferred as it avoids sulphonamide side effects, whilst having similar efficacy in vivo.
Sulphonamides are generally well absorbed after oral administration and are widely distributed. Acetylation and glucuronidation are the most important metabolic pathways.
They may precipitate in acid urine. They frequently cause unwanted side effects, including hypersensitivity reactions such as rashes, fever and serum sickness-like syndrome and Stevens–Johnson syndrome (see Chapter 12). Rarely, agranu- locytosis, megaloblastic, aplastic or haemolytic anaemia and thrombocytopenia occur. Sulphonamides are oxidants and can precipitate haemolytic anaemia in glucose-6-phosphate dehydrogenase (G6PD)-deficient individuals.
Sulphonamides potentiate the action of sulphonylureas, oral anticoagulants, phenytoinandmethotrexatedue to inhi- bition of their metabolism.
Trimethoprimis well absorbed, highly lipid soluble and widely distributed. At least 65% is eliminated unchanged in the urine. Trimethoprimcompetes for the same renal clear- ance pathway as creatinine. It is generally well tolerated, but occasionally causes gastro-intestinal disturbances, skin reac- tions and (rarely) bone marrow depression. Additionally, the high doses used in the management of Pneumocystispneumonia in immunosuppressed patients cause vomiting (which can be improved by prophylactic anti-emetics), a higher incidence of serious skin reactions, hepatitis and thrombocytopenia.
QUINOLONES
Nalidixic acidwas available for many years, but poor tissue distribution and adverse effects limited its use to a second- or third-line treatment for urinary tract infections. Changes to the 330 ANTIBACTERIAL DRUGS