651
interactions and, should the therapy prove to be ineffective, there must be a delay before other antidepressants can be substituted.
rapidly followed to market by (McNeill) and sertraline (Pfizer). Fluvoxamine, launched in some European countries and lately in Canada, generally has not done well, but there are high hopes for sertraline. The sertraline molecule was discovered in the USA and developed in the UK, but the drug is currently marketed only in the UK (’Lustral’); licensing in North America and the antipodes is expected in the next twelve months. How will this agent fare? There are some pharmaceutical precedents-eg, ranitidine replacing cimetidine for peptic ulcer, and glibenclamide replacing tolbutamide for mild diabetes. Perhaps it is more pertinent to ask what has been happening in the antidepression Fluoxetine
was
fluvoxamine
business overall. What are some of the past and future
trends? Those with
a
long
memory will recall that
our
had only amphetamines and barbiturates for depression, with electroconvulsive therapy in their later years. Almost half a century ago the monoamine oxidase inhibitors were introduced, followed by the heterocyclic antidepressants; these drugs helped our parents to an extraordinary degree. How do they work? The tertiary amines, such as amitryptyline, are potent inhibitors of serotonin and noradrenaline uptake whereas the secondary amines, such as nortriptyline, inhibit noradrenaline alone. The new 5-HT uptake blockers are one of two important developments in antidepressant therapy; the other is RIMA (reversible inhibitor of monoamine oxidase A-type), as exemplified by moclobemide (P-chloroN-2-morpholino-ethyl-benzamide, Hoffmann-La Roche). The modem 5-HT uptake blockers are certainly more pleasant for patients than the heterocyclics in that they do not dry the mouth, plug the bowel, over-sedate, or cause dizziness. They are not cardiotoxic and generally cannot be used for self-destruction. However, these drugs are not necessarily more efficacious or faster acting than their
grandparents
predecessors. Sertraline (1-aminotetrahydronaphthalene) is in the UK for acute and chronic treatment approved of depression, and is the first and only antidepressant approved and marketed for prophylaxis against recurrence of depression. Its in-vitro potency exceeds, by many times, that of similar drugs.3 The daily dose is 50 mg, although a maximum of 200 mg may be given; half-life is 26 hours; and peak plasma concentration is attained in 6-8 hours. Thus, should the drug fail, less time has to pass, by comparison with fluoxetine, before another antidepressant can be introduced. It does not have cardiovascular, anticholinergic, antidopaminergic, convulsant, or monoamineoxidase-inhibiting effects. Sertraline still has to stand against other 5-HT uptake blockers in terms of efficacy, pharmacokinetics, side-effect profile, and
and also has to compete with the RIMA agents.4 Unlike the irreversible monoamine oxidase inhibitors, moclobemide has a half-life of only 2 hours, and monoamine oxidase activity recovers completely in 24 hours. This drug is believed to be noradrenergic and not dopaminergic. Since there are no important dietary restrictions, moclobemide is easier to prescribe than the irreversible inhibitors. There is evidence that moclobemide may be as effective as imipramine in endogenous depression and, apart from possible insomnia and headache, the new agent has fewer side-effects. During the next decade it is likely that the 5-HT uptake blockers and the RIMA drugs, with their relatively benign side-effect profiles, will supplant the heterocyclic antidepressants. Since the 1-year prevalence for affective disorders of all kinds is at least 10% for the general population, the market potential is huge. Sertraline and fluoxetine are produced by companies based in North America whereas moclobemide is produced by a European company. Like many of their predecessors, these drugs are being introduced at different times in different countries depending on the vagaries of national licensing procedures. This makes for odd discussion at conferences since only some of the participants will have had any experience with the product. Nevertheless, no one doubts that downmood can be
cost
upmarket. 1. Editorial. 5-HT blockers and all that. Lancet 1990; 336: 345-46. 2. Prozac and suicide: open verdict, 2. Economist 1991; 318, no 7690: 76. 3. Doogan DP, Caillard V. Sertraline: a new antidepressant. J Clin Psychiatry 1988; 49 (suppl 8): 46-51. 4. Priest RG, ed. Depression and reversible monoamine oxidase inhibitors—new perspectives. Br J Psychiatry 1989; 155 (suppl 6).
Mycoplasma pneumoniae Mycoplasma pneumoniae is an important cause of community-acquired pneumonia, especially during epidemics, which arise every four years or so. In the UK, a joint British Thoracic Society/Public Health Laboratory Service study of community-acquired pneumonia in adults in 1982-83 showed that M pneumoniae was responsible for 18% of cases and was the most commonly identified organism after Streptococcus pneumoniae, which was associated with 34%.1 An M pneumoniae epidemic is now again underway in Europe, and will probably last for 18 months to 2 years. Infections arise throughout the year, and spread is usually slow. The incubation period ranges from 2 to 3 weeks. Infection is most commonly reported in children and young adults. Young children experience primary infection, but reinfection can occur in older patients with detectable M pneumoniae antibody.2 Reinfection accounts for most cases in patients over 45 years, and may be associated with severe symptoms.3 The range of illness associated with M pneumoniae extends from
652
mild upper respiratory tract symptoms to pneumonia. Although 25% of M pneumoniae infections are symptomless, about 75% of reported cases are of lower respiratory tract infection.4 Prospective studies show that pneumonia develops in 3-10% of infected patients. In the BTS/PHLS study, M pneumoniae pneumonia was fatal in 4 of 81 patients, none of whom had received appropriate antibiotics before admission to hospital.1 Coughsand tracheobronchitis6 are the commonest features of M pneumoniae infection but cannot distinguish M pneumoniae disease from that due to other common respiratory pathogens. Laboratory diagnosis of M pneumoniae infection is therefore important so that appropriate antibiotic treatment may be initiated. Most laboratories use serological techniques to diagnose M pneumoniae infection. The complement fixation test (CFT) is used by many laboratories, even though non-specific reactions may arise.’7 Inconclusive results, especially moderately raised titres, are common and may be the result of infection several years previously. However, a rise in M pneumoniae CFT antibody titre of more than four fold in paired serum samples is usually thought to be good evidence of recent infection. Newer antibody tests such as particle agglutination and enzyme-linked immunosorbent assays provide a more reliable indication of recent infection. M pneumoniae IgM is a reliable indicator of recent infection, but since this antibody is produced less frequently during reinfection, a negative result does not exclude recent infection, especially in patients over the age of 45. M pneumoniae IgA is a reliable indicator of recent infection,3but this assay is not generally available. M pneumoniae is a fastidious organism, and culture is available in only a few laboratories. Although isolation is difficult and too slow to be clinically relevant, it is regarded as a diagnostic gold standard, especially during the evaluation of serological methods. The organism may persist in the respiratory tract in convalescent patients, despite the use of appropriate antibiotics.8 Other means of diagnosing infection include detection of M pneumoniae antigen in sputum and nasopharyngeal aspirates by use of indirect immunofluorescence with monoclonal antibodies and M pneumoniae ribosomal RNA may be detected with cDNA probes,i° and the polymerase chain reaction has been used to detect M pneumoniae DNA. These techniques are used routinely in only a few specialised laboratories, and there have been few detailed reports of their usefulness. The M pneumoniae antigen EIA reported by Kok et al9 in Australia has a sensitivity of 90 % when compared with culture. The same group of workers reported that the ’Gen- Probe’ assay was more sensitive than their EIA, but they found these tests 10-100 times less sensitive than culture.10 Others have reported similar results." Harris et al’O concluded that
enzyme-linked immunoassay (EIA).9
culture alone should not be the gold standard when tests are compared for their usefulness in detecting M pneumoniae infection; it is also important to take account of culture-negative patients who have good serological evidence of recent infection. Tetracycline and macrolides such as erythromycin are the antibiotics of choice for treating M pneumoniae infections,12 which are resistant to all penicillins, cephalosporins, and trimethoprim. Although antibiotic-resistant genital mycoplasma strains have been reported,12,13 few tetracycline-resistant or erythromycin-resistant strains of M pneumoniae have been found and these are not thought to be clinically important. Pneumococci remain the commonest cause of pneumonia; but, for the next year, M pneumoniae will be responsible for up to 20% of community-acquired cases in all age groups in Europe. Erythromycin resistance in pneumococci is increasing but is still rare (less than 5 % 14 in the UK, but higher in the rest of Europe). Penicillin resistance is only slightly rarer. Consideration should therefore be given to the sole use of erythromycin or addition of erythromycin to a penicillin as antibiotic treatment for community-acquired pneumonia for the coming year across the continent. 1. Research Committee of the British Thoracic Society and the Public Health Laboratory Service. Community-acquired pneumonia in adults in British hospitals in 1982-83: a survey of aetiology, mortality, prognostic factors and outcome. QJ Med 1987; 62: 195-220. 2. Foy HM, Kenny GE, Sefi R, Ochs HD, Allan ID. Second attacks of pneumonia due to Mycoplasma pneumoniae. J Infect Dis 1977; 135: 673-77. 3. Sillis M. The limitation of IgM assays in the serological diagnosis of Mycoplasma pneumoniae infections. J Med Microbiol 1990; 33: 253-58. 4. Surveillance of mycoplasma infections, 1980-90. Commun Dis Rep 1990; 46.
5. Foy HM, Kenny GE, McMahan R, Mansy AM, Grayston JT. Mycoplasma pneumoniae pneumonia in an urban area. JAMA 1970; 214: 1666-72.
6. Komoroff AL, Aronson MD, Pass TM, Ervin CT, Brandt WT. Serological evidence of chlamydial and mycoplasmal pharyngitis in adults. Science 1984; 222: 927-37. 7. Pönkä A, Pönkä T, Sarna S, Penttinen K. Questionable specificity of lipid antigen in the Mycoplasma pneumoniae complement fixation test in patients with extrapulmonary manifestations. J Infect 1981; 3: 332-38. 8. Smith CB, Friedewald WT, Chanock RM. Shedding of Mycoplasma pneumoniae after tetracycline and erythromycin therapy. N Engl J Med
1967; 276: 1172-75. 9. Kok TW, Varkanis G, Marmion BP, Martin J, Esterman A. Laboratory diagnosis of Mycoplasma pneumoniae infection. 1. Direct detection of antigen in respiratory exudates by enzyme immunoassay. Epidemiol Infect 1988; 101: 669-84. 10. Harris R, Marmion BP, Varkanis G, Kok T, Lunn B, Martin J. Laboratory diagnosis of Mycoplasma pneumoniae infection. 2. Comparison of methods for the direct detection of specific antigen or nucleic acid sequences in respiratory exudates. Epidemiol Infect 1988; 101: 685-94. 11. Dular R, Kajioka R, Kasatiya S. Comparison of Gen-Probe commercial kit and culture technique for the diagnosis of Mycoplasma pneumonia infection. J Clin Microbiol 1988; 26: 1068. 12. Rylander M, Hallander HO. In vitro comparison of the activity of doxycycline, tetracycline, erythromycin and a new macrolide CP-62,993 against Mycoplasma pneumoniae, Mycoplasma hominis and Ureaplasma urealyticum. Scand J Infect Dis 1988; 3 (suppl): 12-17. 13. Bébar C, Cantet P, Renaudin H, Quentin C. Activité comparée de la minocycline et de la doxycycline sur les mycoplasmes pathogènes pour l’homme. Pathol Biol 1985; 33: 577-80. 14. Spencer RC, Wheat PF, Magee JT, Brown EH. Erythromycin resistance in streptococci. Lancet 1989; i: 168.
interactions and, should the therapy prove to be ineffective, there must be a delay before other antidepressants can be substituted.
rapidly followed to market by (McNeill) and sertraline (Pfizer). Fluvoxamine, launched in some European countries and lately in Canada, generally has not done well, but there are high hopes for sertraline. The sertraline molecule was discovered in the USA and developed in the UK, but the drug is currently marketed only in the UK (’Lustral’); licensing in North America and the antipodes is expected in the next twelve months. How will this agent fare? There are some pharmaceutical precedents-eg, ranitidine replacing cimetidine for peptic ulcer, and glibenclamide replacing tolbutamide for mild diabetes. Perhaps it is more pertinent to ask what has been happening in the antidepression Fluoxetine
was
fluvoxamine
business overall. What are some of the past and future
trends? Those with
a
long
memory will recall that
our
had only amphetamines and barbiturates for depression, with electroconvulsive therapy in their later years. Almost half a century ago the monoamine oxidase inhibitors were introduced, followed by the heterocyclic antidepressants; these drugs helped our parents to an extraordinary degree. How do they work? The tertiary amines, such as amitryptyline, are potent inhibitors of serotonin and noradrenaline uptake whereas the secondary amines, such as nortriptyline, inhibit noradrenaline alone. The new 5-HT uptake blockers are one of two important developments in antidepressant therapy; the other is RIMA (reversible inhibitor of monoamine oxidase A-type), as exemplified by moclobemide (P-chloroN-2-morpholino-ethyl-benzamide, Hoffmann-La Roche). The modem 5-HT uptake blockers are certainly more pleasant for patients than the heterocyclics in that they do not dry the mouth, plug the bowel, over-sedate, or cause dizziness. They are not cardiotoxic and generally cannot be used for self-destruction. However, these drugs are not necessarily more efficacious or faster acting than their
grandparents
predecessors. Sertraline (1-aminotetrahydronaphthalene) is in the UK for acute and chronic treatment approved of depression, and is the first and only antidepressant approved and marketed for prophylaxis against recurrence of depression. Its in-vitro potency exceeds, by many times, that of similar drugs.3 The daily dose is 50 mg, although a maximum of 200 mg may be given; half-life is 26 hours; and peak plasma concentration is attained in 6-8 hours. Thus, should the drug fail, less time has to pass, by comparison with fluoxetine, before another antidepressant can be introduced. It does not have cardiovascular, anticholinergic, antidopaminergic, convulsant, or monoamineoxidase-inhibiting effects. Sertraline still has to stand against other 5-HT uptake blockers in terms of efficacy, pharmacokinetics, side-effect profile, and
and also has to compete with the RIMA agents.4 Unlike the irreversible monoamine oxidase inhibitors, moclobemide has a half-life of only 2 hours, and monoamine oxidase activity recovers completely in 24 hours. This drug is believed to be noradrenergic and not dopaminergic. Since there are no important dietary restrictions, moclobemide is easier to prescribe than the irreversible inhibitors. There is evidence that moclobemide may be as effective as imipramine in endogenous depression and, apart from possible insomnia and headache, the new agent has fewer side-effects. During the next decade it is likely that the 5-HT uptake blockers and the RIMA drugs, with their relatively benign side-effect profiles, will supplant the heterocyclic antidepressants. Since the 1-year prevalence for affective disorders of all kinds is at least 10% for the general population, the market potential is huge. Sertraline and fluoxetine are produced by companies based in North America whereas moclobemide is produced by a European company. Like many of their predecessors, these drugs are being introduced at different times in different countries depending on the vagaries of national licensing procedures. This makes for odd discussion at conferences since only some of the participants will have had any experience with the product. Nevertheless, no one doubts that downmood can be
cost
upmarket. 1. Editorial. 5-HT blockers and all that. Lancet 1990; 336: 345-46. 2. Prozac and suicide: open verdict, 2. Economist 1991; 318, no 7690: 76. 3. Doogan DP, Caillard V. Sertraline: a new antidepressant. J Clin Psychiatry 1988; 49 (suppl 8): 46-51. 4. Priest RG, ed. Depression and reversible monoamine oxidase inhibitors—new perspectives. Br J Psychiatry 1989; 155 (suppl 6).
Mycoplasma pneumoniae Mycoplasma pneumoniae is an important cause of community-acquired pneumonia, especially during epidemics, which arise every four years or so. In the UK, a joint British Thoracic Society/Public Health Laboratory Service study of community-acquired pneumonia in adults in 1982-83 showed that M pneumoniae was responsible for 18% of cases and was the most commonly identified organism after Streptococcus pneumoniae, which was associated with 34%.1 An M pneumoniae epidemic is now again underway in Europe, and will probably last for 18 months to 2 years. Infections arise throughout the year, and spread is usually slow. The incubation period ranges from 2 to 3 weeks. Infection is most commonly reported in children and young adults. Young children experience primary infection, but reinfection can occur in older patients with detectable M pneumoniae antibody.2 Reinfection accounts for most cases in patients over 45 years, and may be associated with severe symptoms.3 The range of illness associated with M pneumoniae extends from
652
mild upper respiratory tract symptoms to pneumonia. Although 25% of M pneumoniae infections are symptomless, about 75% of reported cases are of lower respiratory tract infection.4 Prospective studies show that pneumonia develops in 3-10% of infected patients. In the BTS/PHLS study, M pneumoniae pneumonia was fatal in 4 of 81 patients, none of whom had received appropriate antibiotics before admission to hospital.1 Coughsand tracheobronchitis6 are the commonest features of M pneumoniae infection but cannot distinguish M pneumoniae disease from that due to other common respiratory pathogens. Laboratory diagnosis of M pneumoniae infection is therefore important so that appropriate antibiotic treatment may be initiated. Most laboratories use serological techniques to diagnose M pneumoniae infection. The complement fixation test (CFT) is used by many laboratories, even though non-specific reactions may arise.’7 Inconclusive results, especially moderately raised titres, are common and may be the result of infection several years previously. However, a rise in M pneumoniae CFT antibody titre of more than four fold in paired serum samples is usually thought to be good evidence of recent infection. Newer antibody tests such as particle agglutination and enzyme-linked immunosorbent assays provide a more reliable indication of recent infection. M pneumoniae IgM is a reliable indicator of recent infection, but since this antibody is produced less frequently during reinfection, a negative result does not exclude recent infection, especially in patients over the age of 45. M pneumoniae IgA is a reliable indicator of recent infection,3but this assay is not generally available. M pneumoniae is a fastidious organism, and culture is available in only a few laboratories. Although isolation is difficult and too slow to be clinically relevant, it is regarded as a diagnostic gold standard, especially during the evaluation of serological methods. The organism may persist in the respiratory tract in convalescent patients, despite the use of appropriate antibiotics.8 Other means of diagnosing infection include detection of M pneumoniae antigen in sputum and nasopharyngeal aspirates by use of indirect immunofluorescence with monoclonal antibodies and M pneumoniae ribosomal RNA may be detected with cDNA probes,i° and the polymerase chain reaction has been used to detect M pneumoniae DNA. These techniques are used routinely in only a few specialised laboratories, and there have been few detailed reports of their usefulness. The M pneumoniae antigen EIA reported by Kok et al9 in Australia has a sensitivity of 90 % when compared with culture. The same group of workers reported that the ’Gen- Probe’ assay was more sensitive than their EIA, but they found these tests 10-100 times less sensitive than culture.10 Others have reported similar results." Harris et al’O concluded that
enzyme-linked immunoassay (EIA).9
culture alone should not be the gold standard when tests are compared for their usefulness in detecting M pneumoniae infection; it is also important to take account of culture-negative patients who have good serological evidence of recent infection. Tetracycline and macrolides such as erythromycin are the antibiotics of choice for treating M pneumoniae infections,12 which are resistant to all penicillins, cephalosporins, and trimethoprim. Although antibiotic-resistant genital mycoplasma strains have been reported,12,13 few tetracycline-resistant or erythromycin-resistant strains of M pneumoniae have been found and these are not thought to be clinically important. Pneumococci remain the commonest cause of pneumonia; but, for the next year, M pneumoniae will be responsible for up to 20% of community-acquired cases in all age groups in Europe. Erythromycin resistance in pneumococci is increasing but is still rare (less than 5 % 14 in the UK, but higher in the rest of Europe). Penicillin resistance is only slightly rarer. Consideration should therefore be given to the sole use of erythromycin or addition of erythromycin to a penicillin as antibiotic treatment for community-acquired pneumonia for the coming year across the continent. 1. Research Committee of the British Thoracic Society and the Public Health Laboratory Service. Community-acquired pneumonia in adults in British hospitals in 1982-83: a survey of aetiology, mortality, prognostic factors and outcome. QJ Med 1987; 62: 195-220. 2. Foy HM, Kenny GE, Sefi R, Ochs HD, Allan ID. Second attacks of pneumonia due to Mycoplasma pneumoniae. J Infect Dis 1977; 135: 673-77. 3. Sillis M. The limitation of IgM assays in the serological diagnosis of Mycoplasma pneumoniae infections. J Med Microbiol 1990; 33: 253-58. 4. Surveillance of mycoplasma infections, 1980-90. Commun Dis Rep 1990; 46.
5. Foy HM, Kenny GE, McMahan R, Mansy AM, Grayston JT. Mycoplasma pneumoniae pneumonia in an urban area. JAMA 1970; 214: 1666-72.
6. Komoroff AL, Aronson MD, Pass TM, Ervin CT, Brandt WT. Serological evidence of chlamydial and mycoplasmal pharyngitis in adults. Science 1984; 222: 927-37. 7. Pönkä A, Pönkä T, Sarna S, Penttinen K. Questionable specificity of lipid antigen in the Mycoplasma pneumoniae complement fixation test in patients with extrapulmonary manifestations. J Infect 1981; 3: 332-38. 8. Smith CB, Friedewald WT, Chanock RM. Shedding of Mycoplasma pneumoniae after tetracycline and erythromycin therapy. N Engl J Med
1967; 276: 1172-75. 9. Kok TW, Varkanis G, Marmion BP, Martin J, Esterman A. Laboratory diagnosis of Mycoplasma pneumoniae infection. 1. Direct detection of antigen in respiratory exudates by enzyme immunoassay. Epidemiol Infect 1988; 101: 669-84. 10. Harris R, Marmion BP, Varkanis G, Kok T, Lunn B, Martin J. Laboratory diagnosis of Mycoplasma pneumoniae infection. 2. Comparison of methods for the direct detection of specific antigen or nucleic acid sequences in respiratory exudates. Epidemiol Infect 1988; 101: 685-94. 11. Dular R, Kajioka R, Kasatiya S. Comparison of Gen-Probe commercial kit and culture technique for the diagnosis of Mycoplasma pneumonia infection. J Clin Microbiol 1988; 26: 1068. 12. Rylander M, Hallander HO. In vitro comparison of the activity of doxycycline, tetracycline, erythromycin and a new macrolide CP-62,993 against Mycoplasma pneumoniae, Mycoplasma hominis and Ureaplasma urealyticum. Scand J Infect Dis 1988; 3 (suppl): 12-17. 13. Bébar C, Cantet P, Renaudin H, Quentin C. Activité comparée de la minocycline et de la doxycycline sur les mycoplasmes pathogènes pour l’homme. Pathol Biol 1985; 33: 577-80. 14. Spencer RC, Wheat PF, Magee JT, Brown EH. Erythromycin resistance in streptococci. Lancet 1989; i: 168.
