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Pharmacological treatment of bacterial infections of the respiratory tract
PHARMACOLOGY
Pharmacological treatment of bacterial infections of the respiratory tract
Stages of peptidoglycan synthesis in the formation of the bacterial cell wall a Intracellular stages Tripeptide Aminosugar 1
Roger C Small Aminosugar 2
The treatments in this article are those recommended in the British National Formulary (edition 49). Any treatment should take into account factors such as the patient’s history, the treatment situation (community or hospital-based medicine) and whether a bacteriological diagnosis has been made (causative microorganism; presence or absence of drug-resistant strains).
Racemase
Cell membrane
D-alanine
Synthetase β-lactam antibiotics are structural analogues
D-alanylD-alanine
Cytosol
Aminosugars-peptide-D-Ala-D-Ala (soluble precursor of peptidoglycan)
Extracellular milieu
Epiglottitis caused by Haemophilus influenzae The recommended treatment for epiglottitis caused by H. influenzae is intravenous cefotaxime or chloramphenicol.
b Stages occurring within the cell membrane
Cefotaxime is a third-generation cephalosporin. Its mechanism of antibacterial action is similar to that of penicillin. The cephalosporins and penicillins are β-lactam antibiotics and, as such, are structural analogues of D-alanyl-D-alanine (Figure 1a). These drugs form covalent bonds with transpeptidases (Figure 1b) and carboxypeptidases (penicillin-binding proteins) and thereby inhibit the transpeptidase reaction in the biochemical pathway by which the peptidoglycan of the bacterial cell wall is synthesized. The transpeptidase reaction occurs outside the cell membrane and involves the formation of peptide cross-links (Figure 1c) between the tetrapeptide side-chains of muramic acid molecules. Since the cell wall normally protects the bacterium from the osmotic effects of its environment, interruption of cell wall synthesis by β-lactam antibiotics leads to the influx of water into the bacterial cell, with subsequent cell swelling and rupture. In some bacteria, the attachment of cephalosporins or penicillins to penicillin-binding proteins disinhibits autolytic enzymes. The activation of autolytic enzymes can therefore contribute to the bactericidal action of these drugs. In contrast to bacteria, mammalian cells do not possess cell walls. The antibacterial action of β-lactam antibiotics thus exhibits selectivity with a qualitative biochemical basis. Compared with the second-generation cephalosporins, cefotaxime has less activity against Gram-positive bacteria but more activity against Gram-negative bacteria. It has some activity against pseudomonads. Following its intravenous administration, cefotaxime is widely distributed throughout the body and is able to cross the blood–brain barrier. Its plasma half-life is 2 hours and excretion is mainly by renal tubular secretion. The unwanted effects of cefotaxime include diarrhoea and allergic reactions.
Cytosol Cell membrane
Phospholipid transporter
Extracellular milieu
Aminosugar units D-alanylD-alanine terminal of peptide sidechain; site of action of transpeptidase (penicillin binding protein)
Transport of precursor molecule to outer face of cell membrane and its assembly into the repeating aminosugar units of the linear peptidoglycan strand
c Extracellular stages: polymerization Cytosolic side of cell membrane
Cell wall Peptide cross-links
Strands of alternating aminosugars
Roger C Small is Honorary Reader in Pharmacology at the University of Manchester, UK. He graduated in pharmacy from Manchester University and studied pharmacology at postgraduate level there. His research interests include the electrophysiology of airways smooth muscle and the actions of novel and established anti-asthma drugs.
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L-alanine
Pentapeptide
β-lactam antibiotics prevent cross-link formation
1
380
© 2005 The Medicine Publishing Company Ltd
PHARMACOLOGY
Chloramphenicol has such serious haematological unwanted effects that its systemic use should be reserved for the treatment of life-threatening conditions. Epiglottitis caused by H. influenzae can lead to obstruction of the respiratory tract and its treatment with intravenously administered chloramphenicol may be justified. Chloramphenicol binds to the 50S subunit of the bacterial ribosome, thereby inhibiting the transpeptidation step in bacterial protein synthesis (Figure 2). To some extent chloramphenicol can also bind to the 70S ribosomes in mammalian cells and may thus inhibit mitochondrial protein synthesis. The antimicrobial action of chloramphenicol therefore exhibits selectivity with a quantitative biochemical basis. Chloramphenicol has a wide spectrum of bacteristatic activity against both Gram-negative and Gram positive organisms. However, it exerts bactericidal activity against H. influenzae. Resistance to chloramphenicol reflects the bacterial production of the enzyme chloramphenicol acetyltransferase. Following its intravenous administration, chloramphenicol is widely distributed throughout the body and penetrates the CSF. Its plasma half-life is 2 hours. Chloramphenicol is mainly biotransformed in the liver but about 12% is excreted unchanged
in the urine. The most serious unwanted effect of chloramphenicol is aplastic anaemia which may prove fatal in 1/50,000 patients. In neonates, chloramphenicol should be administered with particular care, because the immature liver and kidney may result in inadequate biotransformation and inadequate excretion of the unchanged drug, respectively. The resultant high plasma concentrations of choramphenicol may cause ‘grey baby’ syndrome. Exacerbations of chronic bronchitis Streptococcus pneumoniae and H. influenzae are commonly causative in chronic bronchitis. Staphylococcus aureus is a less common cause. Exacerbations of chronic bronchitis may be treated with a broad-spectrum penicillin (e.g. ampicillin, amoxicillin), a tetracycline (e.g. tetracycline, oxytetracycline, doxycycline) or a macrolide antibiotic (e.g. erythromycin, azithromycin, clarithromycin). Ampicillin and amoxicillin (a derivative of ampicillin) interfere with bacterial cell wall synthesis as described above for cefotaxime. They are effective against certain Gram-positive and Gram-negative organisms. Both are inactivated by β-lactamases including those produced by Staph. aureus. Most staphylococci are resistant to ampicillin and amoxicillin. About 15% of strains of H. influenzae are also resisitant to these β-lactam antibiotics. Amoxicillin (in the form of co-amoxiclav) can be prescribed in combination with the β-lactamase inhibitor, clavulanic acid. This renders amoxicillin effective against strains of Staph. aureus, H. influenzae and Klebsiella species that would otherwise be resistant. Ampicillin and amoxicillin are both absorbed from the gastrointestinal tract, though absorption of ampicillin may be impaired by the presence of food in the stomach. Both agents have a plasma half-life of 80 min. Ampicillin is excreted in the bile and both agents are actively secreted into the urine. Unwanted effects of ampicillin and amoxicillin include diarrhoea, maculopapular rashes and the allergic reactions characteristic of penicillins. Co-amoxiclav can cause cholestatic jaundice.
Mechanisms by which some antibiotics interfere with bacterial protein synthesis Impairment of function of 30S subunit of ribosome Codon number
1
2
3
4
5
6
7
8 mRNA
30S subunit of ribosome
tRNA5
Gentamicin Tetracyclines
tRNA4 50S subunit of ribosome
Amino acid
The tetracyclines are broad-spectrum antibiotics that are actively accumulated by susceptible microorganisms. Bacteria can become resistant to the tetracyclines by developing active extrusion processes that reduce the antibiotic concentration in the microbial cell. By binding to the acceptor site on the 30S subunit of the bacterial ribosome, the tetracyclines prevent the binding of aminoacyl-tRNA and therefore interrupt protein synthesis (Figure 2). The tetracyclines have a similar effect on the 70S ribosomes in the mitochondria of mammalian cells. For this reason, the antibacterial action of the tetracyclines has selectivity with a quantitative rather than a qualitative biochemical basis. The tetracyclines exert bacteriostatic effects against a wide range of Gram-positive and Gram-negative microorganisms including Mycoplasma pneumoniae, Rickettsia, Chlamydia and some protozoa. Absorption of tetracyclines from the gastrointestinal tract is variable. Only 30% of an oral dose of chlortetracycline is absorbed; this rises to 60–80% for tetracycline and oxytetracycline. For doxycycline and minocycline, absorption is virtually complete. The tetracyclines tend to form chelates with metal ions, therefore their absorption from the gastrointestinal tract is inhibited by ingestion of Ca2+ (in dairy products), Al2+, Mg2+ (in antacids) and ferrous sulphate. Following absorption, the tetracyclines are widely distributed throughout the body and can cross the placenta
Inhibition of peptide bond formation
Chloramphenicol
Inhibition of ribosomal translocation Ribosome moves along mRNA by one codon Erythromycin
2
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PHARMACOLOGY
to reach the fetus. They are excreted in the bile (the main route for doxycycline) and in the urine. Unwanted effects include gastrointestinal disturbances (of which the worst is pseudomembranous colitis), skin rashes, allergic reactions and hepatotoxicity. Tetracycline-induced inhibition of protein synthesis may lead to the accumulation of nitrogenous waste products in the blood and aggravate renal failure. Tetracyclines should not be prescribed to pregnant women or children under 12 years because they form chelates with Ca2+ causing bone deformities and staining of teeth.
a lactamase-resistant penicillin, to the treatment regimen. Flucloxacillin is resistant to gastric acid, but is poorly absorbed after oral administration. Food impairs absorption of flucloxacillin from the gastrointestinal tract, but it can be administered by intramuscular or intravenous injection. Protracted treatment with flucloxacillin (over 2 weeks) has been associated with cholestatic jaundice. Severe community-acquired pneumonia of unknown aetiology A macrolide antibiotic (e.g. erythromycin) in combination with cefuroxime or cefotaxime is recommended for the treatment of severe, community-acquired pneumonia of unknown aetiology. Cefuroxime is a second-generation cephalosporin that is relatively resistant to β-lactamase. Compared with the first-generation cephalosporins, cefuroxime is less effective against Gram-positive organisms but more effective against Gram-negative organisms. Cefuroxime can be administered orally or parenterally. It is widely distributed in the body and can cross the blood–brain barrier. Its plasma half-life is 90 min. Cefuroxime is mainly eliminated by active secretion in the kidney. If Staph. aureus is suspected as a cause of this type of pneumonia, flucloxacillin should be added to the treatment regimen.
Macrolide antibiotics (erythromycin, azithromycin, clarithromycin) bind to the 50S subunit of the bacterial ribosome, thus inhibiting the translocation step in bacterial protein synthesis (Figure 2). This antibacterial action may be bacteriostatic or bactericidal depending on the antibiotic, its concentration and the target microorganism. The binding site for the macrolides on the subunit of the bacterial ribosome is identical to that of chloramphenicol, and competition may occur. Erythromycin is effective against many Gram-positive bacteria and some Gram-negative organisms. It is useful in patients who are allergic to penicillin. Azithromycin and the active metabolite of clarithromycin are more effective against H. influenzae than is erythromycin. The macrolides are absorbed from the gastrointestinal tract and are widely distributed in the body, though they do not cross the blood–brain barrier. The plasma half-life of erythromycin is 90 min and that for clarithromycin and azithromycin is significantly longer. Azithromycin is relatively resistant to biotransformation, but erythromycin is deactivated in the liver, and clarithromycin is converted to an active metabolite. Unwanted effects of the macrolides include gastrointestinal disturbances. Erythromycin has also been reported to cause skin rashes and cholestatic jaundice.
Suspected atypical pneumonia Suspected atypical pneumonia may be treated with a macrolide antibiotic (e.g. erythromycin). If C. pneumoniae or M. pneumoniae is the suspected cause, a tetracycline may be used as an alternative to the macrolide. If Legionella pneumophila is suspected to be the causative microorganism, rifampicin should be added to the treatment with a macrolide. Rifampicin is an antibiotic that directly interferes with DNAdependent RNA polymerase in bacteria, but does not affect the homologous enzyme in the nuclei of mammalian cells. It enters phagocytic cells and is therefore active against intracellular microorganisms. It is bactericidal against a variety of bacteria including L. pneumophila and Mycobacterium tuberculosis. However, resistance to rifampicin can develop quickly, through the production of an altered DNA-dependent RNA polymerase. Rifampicin is suitable for oral administration and is widely distributed throughout the body. The plasma half-life is 1–5 hours and rifampicin is excreted partly in the bile (as metabolites) and partly in the urine. Rifampicin imparts an orange–red colour to secretions such as tears and urine. Unwanted effects of rifampicin include hepatotoxicity and gastrointestinal disturbances. It induces hepatic microsomal enzymes and may therefore reduce the efficiency of oestrogen-containing oral contraceptives, corticosteroids, sulphonylureas, warfarin and phenytoin.
Uncomplicated, community-acquired pneumonia Uncomplicated, community-acquired pneumonia is caused by S. pneumoniae (30–50% of cases), H. influenzae (5–15%), M. pneumoniae (0–20%, according to a 4-year cycle of epidemics), Chlamydia pneumoniae (about 10%) and Staph. aureus (about 3%, increasing during epidemics of influenza or measles). Klebsiella pneumoniae and Pseudomonas aeruginosa are relatively uncommon causes of community-acquired pneumonia. Uncomplicated, community-acquired pneumonia may be treated with amoxicillin or ampicillin. Alternatively, if the patient is allergic to penicillins, erythromycin may be used. If an atypical pneumonia is suspected, this macrolide should be used in combination with amoxicillin or ampicillin. If the patient has no history of chest infection, there is a high chance that the causative organism is S. pneumoniae. In this circumstance it may be better to use benzylpenicillin, a highly potent penicillin, rather than amoxicillin or ampicillin. Benzylpenicillin is bactericidal against some Grampositive cocci and bacilli and also against some Gram-negative cocci. Since benzylpenicillin is hydrolysed by gastric acid, it is administered by intravenous or intramuscular injection. It is widely distributed throughout the body but does not penetrate the CSF unless the meninges are inflamed. Benzylpenicillin is eliminated by renal tubular secretion. Its unwanted effects are characteristic of the penicillins and mainly comprise hypersensitivity reactions. Staph. aureus produces β-lactamase and therefore pneumonia caused by this organism is best managed by adding flucloxacillin,
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Hospital-acquired pneumonia Hospital-acquired pneumonia may be caused by K. pneumoniae (10–20% cases), P. aeruginosa (10–15%), S. pneumoniae (about 10%), Staph. aureus (about 10%) or H. influenzae (about 5%). M. pneumoniae is a relatively uncommon cause. A broad-spectrum cephalosporin (e.g. cefotaxime or ceftazidime) is indicated for the treatment of hospital-acquired pneumonia. If P. aeruginosa infection is suspected, ceftazidime may be useful. Ceftazidime is a third-generation cephalosporin with good activity against P. aeruginosa and other Gram-negative bacteria. It is administered by intramuscular or intravenous injection and 382
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has a plasma half-life of 1.5 hours. It is not metabolized. An antipseudomonal penicillin (e.g. ticarcillin or piperacillin) may be used as an alternative to ceftadizime. Ticarcillin is a carboxypenicillin that is effective against P. aeruginosa and other Gram-negative bacteria. Absorption of ticarcillin from the gastrointestinal tract is poor and it is administered by intravenous infusion. Piperacillin is a ureidopenicillin with a broad spectrum of antibacterial activity. It is more active than ticarcillin against P. aeruginosa. Like ticarcillin, it is poorly absorbed from the gastrointestinal tract and is administered by the intramuscular or intravenous routes. Both ticarcillin and piperacillin are susceptible to β-lactamase. They can be administered together with a β-lactamase inhibitor such as clavulanic acid (ticarcillin) or tazobactam (piperacillin). In the presence of tazobactam, piperacillin is the penicillin that exhibits the broadest spectrum of antimicrobial activity. When hospitalacquired pneumonia causes severe illness, an aminoglycoside such as gentamicin can be added to the treatment regimen.
intracellular microorganisms. Isoniazid is actively accumulated by tubercle bacilli and, following its conversion to an active metabolite, interferes with the synthesis of mycolic acid and thus cell wall synthesis. Mycolic acids are unique to mycobacteria and this helps to explain the selectivity of action not only of isoniazid but also of pyrazinamide and ethambutol (see below). Isoniazid is bacteriostatic for resting microorganisms but bactericidal towards those that are rapidly dividing. If isoniazid is used in the absence of any other antitubercular drug, resistance develops rapidly. The most common resistance mechanism is reduced conversion of the prodrug into the active metabolite. However, cross-resistance between isoniazid and other antitubercular drugs does not occur. Isoniazid is well absorbed from the gastrointestinal tract and widely distributed in the body. It readily penetrates the CSF and diffuses into cell interiors. It is acetylated in the liver at a rate that is genetically determined. Slow acetylators are likely to develop unwanted effects such as peripheral neuropathy and hepatitis. The likelihood of isoniazid-induced neuropathy can be reduced by the co-administration of pyridoxine.
Gentamicin and other aminoglycoside antibiotics enter susceptible bacterial cells by an oxygen-dependent transport process. For this reason they have little effect against anaerobic organisms. Once inside the aerobic bacterial cell, the aminoglycosides bind irreversibly to the 30S subunit of the bacterial ribosome, distorting the subunit so that reading of codons on the mRNA strand is impaired and protein synthesis is interrupted (Figure 2). This leads to the eventual disruption of the bacterial cell membrane. Gentamicin is a highly polar, water-soluble base that is poorly absorbed from the gastrointestinal tract. It is administered by intramuscular or slow intravenous injection. Its distribution is restricted to the extracellular compartment and it penetrates the CSF poorly. Gentamicin is excreted by glomerular filtration. Its unwanted effects are dose-related and include ototoxicity and nephrotoxicity. These unwanted effects are more likely with renal impairment.
Pyrazinamide is relatively specific for mycobacteria. Its bactericidal action involves interference with the gene that encodes for mycobacterial fatty acid synthase. This leads to interruption of mycolic acid synthesis and thus the synthesis of the bacterial cell wall. The action of pyrazinamide proceeds best at a slightly acid pH. Furthermore, Mycobacterium tuberculosis normally resides in an acidic phagosome within a macrophage. These conditions are ideal for the action of pyrazinamide. However, resistance to pyrazinamide develops rapidly when it is used in the absence of any other antitubercular drug. Pyrazinamide is well absorbed from the gastrointestinal tract and is widely distributed throughout the body. It readily penetrates the CSF. Its plasma half-life is 9–10 hours. It is excreted by renal glomerular filtration in the form of metabolites. Unwanted effects include hyperuricaemia, arthralgia and hepatic dysfunction.
Tuberculosis Treatment of tuberculosis requires specialized knowledge, particularly if the infection involves extrapulmonary tissue or drugresistant organisms. The Joint Tuberculosis Committee of the British Thoracic Society has recommended that the treatment of tuberculosis should comprise an initial phase lasting for 2 months and should involve the use of at least three antitubercular drugs. The object of the initial phase of treatment is to reduce the infecting population of mycobacteria as quickly as possible, to minimize the chance of resistant strains emerging. The recommended drugs include rifampicin, isoniazid, pyrazinamide and ethambutol. Ethambutol may be omitted if the risk of isoniazid resistance is low. After the initial phase, the continuation phase of therapy comprises the administration of rifampicin and isoniazid in combination for 4 months. Where resistant organisms are suspected, the continuation phase may involve alternative antitubercular drugs (only first-line agents are considered in this article). Where extrapulmonary infection is present, the continuation phase of treatment may require extension.
Ethambutol is relatively specific for mycobacteria. It is taken up by mycobacterial cells and, after a delay of about 24 hours, it produces a bacteriostatic effect. This involves interference with the activity of arabinosyl transferase enzymes that are involved in cell wall synthesis. Resistance to ethambutol develops rapidly if used in the absence of any other antitubercular drug and results from changes in the gene that encodes for arabinosyl transferase. Ethambutol is well absorbed from the gastrointestinal tract and can penetrate the CSF. Its plasma half-life is 3–4 hours. Ethambutol is partly metabolized but is mainly excreted unchanged in the urine. Unwanted effects include optic neuritis, leading to reduced visual acuity and reduced ability to differentiate between red and green. These changes in vision are reversible, providing that the drug is withdrawn at an early stage. Ethambutol should be avoided, or its dose reduced if there is renal insufficiency. FURTHER READING British National Formulary. 49th ed. London: BMJ Books, and Wallingford: Pharmaceutical Press, 2005. Hardman J G, Limbird L E, Goodman Gilman A, eds. The pharmacological basis of therapeutics. 10th ed. New York: McGraw-Hill, 2001. Rang H P, Dale M M, Ritter J M, Moore P K. Pharmacology. 5th ed. Edinburgh: Churchill Livingstone, 2003.
Rifampicin is described above. It forms a crucial part of any treatment regimen for tuberculosis. Isoniazid is a prodrug that exerts a highly selective action against mycobacteria. It is able to diffuse into mammalian cells to reach
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Pharmacological treatment of bacterial infections of the respiratory tract
Stages of peptidoglycan synthesis in the formation of the bacterial cell wall a Intracellular stages Tripeptide Aminosugar 1
Roger C Small Aminosugar 2
The treatments in this article are those recommended in the British National Formulary (edition 49). Any treatment should take into account factors such as the patient’s history, the treatment situation (community or hospital-based medicine) and whether a bacteriological diagnosis has been made (causative microorganism; presence or absence of drug-resistant strains).
Racemase
Cell membrane
D-alanine
Synthetase β-lactam antibiotics are structural analogues
D-alanylD-alanine
Cytosol
Aminosugars-peptide-D-Ala-D-Ala (soluble precursor of peptidoglycan)
Extracellular milieu
Epiglottitis caused by Haemophilus influenzae The recommended treatment for epiglottitis caused by H. influenzae is intravenous cefotaxime or chloramphenicol.
b Stages occurring within the cell membrane
Cefotaxime is a third-generation cephalosporin. Its mechanism of antibacterial action is similar to that of penicillin. The cephalosporins and penicillins are β-lactam antibiotics and, as such, are structural analogues of D-alanyl-D-alanine (Figure 1a). These drugs form covalent bonds with transpeptidases (Figure 1b) and carboxypeptidases (penicillin-binding proteins) and thereby inhibit the transpeptidase reaction in the biochemical pathway by which the peptidoglycan of the bacterial cell wall is synthesized. The transpeptidase reaction occurs outside the cell membrane and involves the formation of peptide cross-links (Figure 1c) between the tetrapeptide side-chains of muramic acid molecules. Since the cell wall normally protects the bacterium from the osmotic effects of its environment, interruption of cell wall synthesis by β-lactam antibiotics leads to the influx of water into the bacterial cell, with subsequent cell swelling and rupture. In some bacteria, the attachment of cephalosporins or penicillins to penicillin-binding proteins disinhibits autolytic enzymes. The activation of autolytic enzymes can therefore contribute to the bactericidal action of these drugs. In contrast to bacteria, mammalian cells do not possess cell walls. The antibacterial action of β-lactam antibiotics thus exhibits selectivity with a qualitative biochemical basis. Compared with the second-generation cephalosporins, cefotaxime has less activity against Gram-positive bacteria but more activity against Gram-negative bacteria. It has some activity against pseudomonads. Following its intravenous administration, cefotaxime is widely distributed throughout the body and is able to cross the blood–brain barrier. Its plasma half-life is 2 hours and excretion is mainly by renal tubular secretion. The unwanted effects of cefotaxime include diarrhoea and allergic reactions.
Cytosol Cell membrane
Phospholipid transporter
Extracellular milieu
Aminosugar units D-alanylD-alanine terminal of peptide sidechain; site of action of transpeptidase (penicillin binding protein)
Transport of precursor molecule to outer face of cell membrane and its assembly into the repeating aminosugar units of the linear peptidoglycan strand
c Extracellular stages: polymerization Cytosolic side of cell membrane
Cell wall Peptide cross-links
Strands of alternating aminosugars
Roger C Small is Honorary Reader in Pharmacology at the University of Manchester, UK. He graduated in pharmacy from Manchester University and studied pharmacology at postgraduate level there. His research interests include the electrophysiology of airways smooth muscle and the actions of novel and established anti-asthma drugs.
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L-alanine
Pentapeptide
β-lactam antibiotics prevent cross-link formation
1
380
© 2005 The Medicine Publishing Company Ltd
PHARMACOLOGY
Chloramphenicol has such serious haematological unwanted effects that its systemic use should be reserved for the treatment of life-threatening conditions. Epiglottitis caused by H. influenzae can lead to obstruction of the respiratory tract and its treatment with intravenously administered chloramphenicol may be justified. Chloramphenicol binds to the 50S subunit of the bacterial ribosome, thereby inhibiting the transpeptidation step in bacterial protein synthesis (Figure 2). To some extent chloramphenicol can also bind to the 70S ribosomes in mammalian cells and may thus inhibit mitochondrial protein synthesis. The antimicrobial action of chloramphenicol therefore exhibits selectivity with a quantitative biochemical basis. Chloramphenicol has a wide spectrum of bacteristatic activity against both Gram-negative and Gram positive organisms. However, it exerts bactericidal activity against H. influenzae. Resistance to chloramphenicol reflects the bacterial production of the enzyme chloramphenicol acetyltransferase. Following its intravenous administration, chloramphenicol is widely distributed throughout the body and penetrates the CSF. Its plasma half-life is 2 hours. Chloramphenicol is mainly biotransformed in the liver but about 12% is excreted unchanged
in the urine. The most serious unwanted effect of chloramphenicol is aplastic anaemia which may prove fatal in 1/50,000 patients. In neonates, chloramphenicol should be administered with particular care, because the immature liver and kidney may result in inadequate biotransformation and inadequate excretion of the unchanged drug, respectively. The resultant high plasma concentrations of choramphenicol may cause ‘grey baby’ syndrome. Exacerbations of chronic bronchitis Streptococcus pneumoniae and H. influenzae are commonly causative in chronic bronchitis. Staphylococcus aureus is a less common cause. Exacerbations of chronic bronchitis may be treated with a broad-spectrum penicillin (e.g. ampicillin, amoxicillin), a tetracycline (e.g. tetracycline, oxytetracycline, doxycycline) or a macrolide antibiotic (e.g. erythromycin, azithromycin, clarithromycin). Ampicillin and amoxicillin (a derivative of ampicillin) interfere with bacterial cell wall synthesis as described above for cefotaxime. They are effective against certain Gram-positive and Gram-negative organisms. Both are inactivated by β-lactamases including those produced by Staph. aureus. Most staphylococci are resistant to ampicillin and amoxicillin. About 15% of strains of H. influenzae are also resisitant to these β-lactam antibiotics. Amoxicillin (in the form of co-amoxiclav) can be prescribed in combination with the β-lactamase inhibitor, clavulanic acid. This renders amoxicillin effective against strains of Staph. aureus, H. influenzae and Klebsiella species that would otherwise be resistant. Ampicillin and amoxicillin are both absorbed from the gastrointestinal tract, though absorption of ampicillin may be impaired by the presence of food in the stomach. Both agents have a plasma half-life of 80 min. Ampicillin is excreted in the bile and both agents are actively secreted into the urine. Unwanted effects of ampicillin and amoxicillin include diarrhoea, maculopapular rashes and the allergic reactions characteristic of penicillins. Co-amoxiclav can cause cholestatic jaundice.
Mechanisms by which some antibiotics interfere with bacterial protein synthesis Impairment of function of 30S subunit of ribosome Codon number
1
2
3
4
5
6
7
8 mRNA
30S subunit of ribosome
tRNA5
Gentamicin Tetracyclines
tRNA4 50S subunit of ribosome
Amino acid
The tetracyclines are broad-spectrum antibiotics that are actively accumulated by susceptible microorganisms. Bacteria can become resistant to the tetracyclines by developing active extrusion processes that reduce the antibiotic concentration in the microbial cell. By binding to the acceptor site on the 30S subunit of the bacterial ribosome, the tetracyclines prevent the binding of aminoacyl-tRNA and therefore interrupt protein synthesis (Figure 2). The tetracyclines have a similar effect on the 70S ribosomes in the mitochondria of mammalian cells. For this reason, the antibacterial action of the tetracyclines has selectivity with a quantitative rather than a qualitative biochemical basis. The tetracyclines exert bacteriostatic effects against a wide range of Gram-positive and Gram-negative microorganisms including Mycoplasma pneumoniae, Rickettsia, Chlamydia and some protozoa. Absorption of tetracyclines from the gastrointestinal tract is variable. Only 30% of an oral dose of chlortetracycline is absorbed; this rises to 60–80% for tetracycline and oxytetracycline. For doxycycline and minocycline, absorption is virtually complete. The tetracyclines tend to form chelates with metal ions, therefore their absorption from the gastrointestinal tract is inhibited by ingestion of Ca2+ (in dairy products), Al2+, Mg2+ (in antacids) and ferrous sulphate. Following absorption, the tetracyclines are widely distributed throughout the body and can cross the placenta
Inhibition of peptide bond formation
Chloramphenicol
Inhibition of ribosomal translocation Ribosome moves along mRNA by one codon Erythromycin
2
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to reach the fetus. They are excreted in the bile (the main route for doxycycline) and in the urine. Unwanted effects include gastrointestinal disturbances (of which the worst is pseudomembranous colitis), skin rashes, allergic reactions and hepatotoxicity. Tetracycline-induced inhibition of protein synthesis may lead to the accumulation of nitrogenous waste products in the blood and aggravate renal failure. Tetracyclines should not be prescribed to pregnant women or children under 12 years because they form chelates with Ca2+ causing bone deformities and staining of teeth.
a lactamase-resistant penicillin, to the treatment regimen. Flucloxacillin is resistant to gastric acid, but is poorly absorbed after oral administration. Food impairs absorption of flucloxacillin from the gastrointestinal tract, but it can be administered by intramuscular or intravenous injection. Protracted treatment with flucloxacillin (over 2 weeks) has been associated with cholestatic jaundice. Severe community-acquired pneumonia of unknown aetiology A macrolide antibiotic (e.g. erythromycin) in combination with cefuroxime or cefotaxime is recommended for the treatment of severe, community-acquired pneumonia of unknown aetiology. Cefuroxime is a second-generation cephalosporin that is relatively resistant to β-lactamase. Compared with the first-generation cephalosporins, cefuroxime is less effective against Gram-positive organisms but more effective against Gram-negative organisms. Cefuroxime can be administered orally or parenterally. It is widely distributed in the body and can cross the blood–brain barrier. Its plasma half-life is 90 min. Cefuroxime is mainly eliminated by active secretion in the kidney. If Staph. aureus is suspected as a cause of this type of pneumonia, flucloxacillin should be added to the treatment regimen.
Macrolide antibiotics (erythromycin, azithromycin, clarithromycin) bind to the 50S subunit of the bacterial ribosome, thus inhibiting the translocation step in bacterial protein synthesis (Figure 2). This antibacterial action may be bacteriostatic or bactericidal depending on the antibiotic, its concentration and the target microorganism. The binding site for the macrolides on the subunit of the bacterial ribosome is identical to that of chloramphenicol, and competition may occur. Erythromycin is effective against many Gram-positive bacteria and some Gram-negative organisms. It is useful in patients who are allergic to penicillin. Azithromycin and the active metabolite of clarithromycin are more effective against H. influenzae than is erythromycin. The macrolides are absorbed from the gastrointestinal tract and are widely distributed in the body, though they do not cross the blood–brain barrier. The plasma half-life of erythromycin is 90 min and that for clarithromycin and azithromycin is significantly longer. Azithromycin is relatively resistant to biotransformation, but erythromycin is deactivated in the liver, and clarithromycin is converted to an active metabolite. Unwanted effects of the macrolides include gastrointestinal disturbances. Erythromycin has also been reported to cause skin rashes and cholestatic jaundice.
Suspected atypical pneumonia Suspected atypical pneumonia may be treated with a macrolide antibiotic (e.g. erythromycin). If C. pneumoniae or M. pneumoniae is the suspected cause, a tetracycline may be used as an alternative to the macrolide. If Legionella pneumophila is suspected to be the causative microorganism, rifampicin should be added to the treatment with a macrolide. Rifampicin is an antibiotic that directly interferes with DNAdependent RNA polymerase in bacteria, but does not affect the homologous enzyme in the nuclei of mammalian cells. It enters phagocytic cells and is therefore active against intracellular microorganisms. It is bactericidal against a variety of bacteria including L. pneumophila and Mycobacterium tuberculosis. However, resistance to rifampicin can develop quickly, through the production of an altered DNA-dependent RNA polymerase. Rifampicin is suitable for oral administration and is widely distributed throughout the body. The plasma half-life is 1–5 hours and rifampicin is excreted partly in the bile (as metabolites) and partly in the urine. Rifampicin imparts an orange–red colour to secretions such as tears and urine. Unwanted effects of rifampicin include hepatotoxicity and gastrointestinal disturbances. It induces hepatic microsomal enzymes and may therefore reduce the efficiency of oestrogen-containing oral contraceptives, corticosteroids, sulphonylureas, warfarin and phenytoin.
Uncomplicated, community-acquired pneumonia Uncomplicated, community-acquired pneumonia is caused by S. pneumoniae (30–50% of cases), H. influenzae (5–15%), M. pneumoniae (0–20%, according to a 4-year cycle of epidemics), Chlamydia pneumoniae (about 10%) and Staph. aureus (about 3%, increasing during epidemics of influenza or measles). Klebsiella pneumoniae and Pseudomonas aeruginosa are relatively uncommon causes of community-acquired pneumonia. Uncomplicated, community-acquired pneumonia may be treated with amoxicillin or ampicillin. Alternatively, if the patient is allergic to penicillins, erythromycin may be used. If an atypical pneumonia is suspected, this macrolide should be used in combination with amoxicillin or ampicillin. If the patient has no history of chest infection, there is a high chance that the causative organism is S. pneumoniae. In this circumstance it may be better to use benzylpenicillin, a highly potent penicillin, rather than amoxicillin or ampicillin. Benzylpenicillin is bactericidal against some Grampositive cocci and bacilli and also against some Gram-negative cocci. Since benzylpenicillin is hydrolysed by gastric acid, it is administered by intravenous or intramuscular injection. It is widely distributed throughout the body but does not penetrate the CSF unless the meninges are inflamed. Benzylpenicillin is eliminated by renal tubular secretion. Its unwanted effects are characteristic of the penicillins and mainly comprise hypersensitivity reactions. Staph. aureus produces β-lactamase and therefore pneumonia caused by this organism is best managed by adding flucloxacillin,
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Hospital-acquired pneumonia Hospital-acquired pneumonia may be caused by K. pneumoniae (10–20% cases), P. aeruginosa (10–15%), S. pneumoniae (about 10%), Staph. aureus (about 10%) or H. influenzae (about 5%). M. pneumoniae is a relatively uncommon cause. A broad-spectrum cephalosporin (e.g. cefotaxime or ceftazidime) is indicated for the treatment of hospital-acquired pneumonia. If P. aeruginosa infection is suspected, ceftazidime may be useful. Ceftazidime is a third-generation cephalosporin with good activity against P. aeruginosa and other Gram-negative bacteria. It is administered by intramuscular or intravenous injection and 382
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PHARMACOLOGY
has a plasma half-life of 1.5 hours. It is not metabolized. An antipseudomonal penicillin (e.g. ticarcillin or piperacillin) may be used as an alternative to ceftadizime. Ticarcillin is a carboxypenicillin that is effective against P. aeruginosa and other Gram-negative bacteria. Absorption of ticarcillin from the gastrointestinal tract is poor and it is administered by intravenous infusion. Piperacillin is a ureidopenicillin with a broad spectrum of antibacterial activity. It is more active than ticarcillin against P. aeruginosa. Like ticarcillin, it is poorly absorbed from the gastrointestinal tract and is administered by the intramuscular or intravenous routes. Both ticarcillin and piperacillin are susceptible to β-lactamase. They can be administered together with a β-lactamase inhibitor such as clavulanic acid (ticarcillin) or tazobactam (piperacillin). In the presence of tazobactam, piperacillin is the penicillin that exhibits the broadest spectrum of antimicrobial activity. When hospitalacquired pneumonia causes severe illness, an aminoglycoside such as gentamicin can be added to the treatment regimen.
intracellular microorganisms. Isoniazid is actively accumulated by tubercle bacilli and, following its conversion to an active metabolite, interferes with the synthesis of mycolic acid and thus cell wall synthesis. Mycolic acids are unique to mycobacteria and this helps to explain the selectivity of action not only of isoniazid but also of pyrazinamide and ethambutol (see below). Isoniazid is bacteriostatic for resting microorganisms but bactericidal towards those that are rapidly dividing. If isoniazid is used in the absence of any other antitubercular drug, resistance develops rapidly. The most common resistance mechanism is reduced conversion of the prodrug into the active metabolite. However, cross-resistance between isoniazid and other antitubercular drugs does not occur. Isoniazid is well absorbed from the gastrointestinal tract and widely distributed in the body. It readily penetrates the CSF and diffuses into cell interiors. It is acetylated in the liver at a rate that is genetically determined. Slow acetylators are likely to develop unwanted effects such as peripheral neuropathy and hepatitis. The likelihood of isoniazid-induced neuropathy can be reduced by the co-administration of pyridoxine.
Gentamicin and other aminoglycoside antibiotics enter susceptible bacterial cells by an oxygen-dependent transport process. For this reason they have little effect against anaerobic organisms. Once inside the aerobic bacterial cell, the aminoglycosides bind irreversibly to the 30S subunit of the bacterial ribosome, distorting the subunit so that reading of codons on the mRNA strand is impaired and protein synthesis is interrupted (Figure 2). This leads to the eventual disruption of the bacterial cell membrane. Gentamicin is a highly polar, water-soluble base that is poorly absorbed from the gastrointestinal tract. It is administered by intramuscular or slow intravenous injection. Its distribution is restricted to the extracellular compartment and it penetrates the CSF poorly. Gentamicin is excreted by glomerular filtration. Its unwanted effects are dose-related and include ototoxicity and nephrotoxicity. These unwanted effects are more likely with renal impairment.
Pyrazinamide is relatively specific for mycobacteria. Its bactericidal action involves interference with the gene that encodes for mycobacterial fatty acid synthase. This leads to interruption of mycolic acid synthesis and thus the synthesis of the bacterial cell wall. The action of pyrazinamide proceeds best at a slightly acid pH. Furthermore, Mycobacterium tuberculosis normally resides in an acidic phagosome within a macrophage. These conditions are ideal for the action of pyrazinamide. However, resistance to pyrazinamide develops rapidly when it is used in the absence of any other antitubercular drug. Pyrazinamide is well absorbed from the gastrointestinal tract and is widely distributed throughout the body. It readily penetrates the CSF. Its plasma half-life is 9–10 hours. It is excreted by renal glomerular filtration in the form of metabolites. Unwanted effects include hyperuricaemia, arthralgia and hepatic dysfunction.
Tuberculosis Treatment of tuberculosis requires specialized knowledge, particularly if the infection involves extrapulmonary tissue or drugresistant organisms. The Joint Tuberculosis Committee of the British Thoracic Society has recommended that the treatment of tuberculosis should comprise an initial phase lasting for 2 months and should involve the use of at least three antitubercular drugs. The object of the initial phase of treatment is to reduce the infecting population of mycobacteria as quickly as possible, to minimize the chance of resistant strains emerging. The recommended drugs include rifampicin, isoniazid, pyrazinamide and ethambutol. Ethambutol may be omitted if the risk of isoniazid resistance is low. After the initial phase, the continuation phase of therapy comprises the administration of rifampicin and isoniazid in combination for 4 months. Where resistant organisms are suspected, the continuation phase may involve alternative antitubercular drugs (only first-line agents are considered in this article). Where extrapulmonary infection is present, the continuation phase of treatment may require extension.
Ethambutol is relatively specific for mycobacteria. It is taken up by mycobacterial cells and, after a delay of about 24 hours, it produces a bacteriostatic effect. This involves interference with the activity of arabinosyl transferase enzymes that are involved in cell wall synthesis. Resistance to ethambutol develops rapidly if used in the absence of any other antitubercular drug and results from changes in the gene that encodes for arabinosyl transferase. Ethambutol is well absorbed from the gastrointestinal tract and can penetrate the CSF. Its plasma half-life is 3–4 hours. Ethambutol is partly metabolized but is mainly excreted unchanged in the urine. Unwanted effects include optic neuritis, leading to reduced visual acuity and reduced ability to differentiate between red and green. These changes in vision are reversible, providing that the drug is withdrawn at an early stage. Ethambutol should be avoided, or its dose reduced if there is renal insufficiency. FURTHER READING British National Formulary. 49th ed. London: BMJ Books, and Wallingford: Pharmaceutical Press, 2005. Hardman J G, Limbird L E, Goodman Gilman A, eds. The pharmacological basis of therapeutics. 10th ed. New York: McGraw-Hill, 2001. Rang H P, Dale M M, Ritter J M, Moore P K. Pharmacology. 5th ed. Edinburgh: Churchill Livingstone, 2003.
Rifampicin is described above. It forms a crucial part of any treatment regimen for tuberculosis. Isoniazid is a prodrug that exerts a highly selective action against mycobacteria. It is able to diffuse into mammalian cells to reach
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