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Clinical impact of drug resistance
Journal
of Hospital Infection (1988) 11 (Supplement
Clinical
imp$acf
A), 135-141
of drug
resistance
H. P. Lambert Department
of Communicable Diseases, St. George’s Hospital Cranmer Terrace, London S WI 7 ORE
Medical
School,
Introduction Other papers in this Symposium deal with the mechanisms of drug resistance and with the problems of its control. I confine this discussion to an account of the ways in which the spread of resistant organisms has acted as a constraint by limiting, or in some cases totally abrogating, the use of particular agents in prophylaxis and therapy. The very diverse time scale of antibiotic resistance problems makes it necessary to examine changing patterns of usage over a period of several decades. Traditionally community-acquired and hospital-acquired infections are considered separately, but ample epidemiological evidence now testifies to the ease with which bacterial populations in the community and hospital interact. It is, nevertheless, convenient to deal with the two main epidemiological groupings separately and, because so much of the Conference is concerned with hospital infection, the main emphasis here will be on infections arising in the community. Meningitis The use of sulphonamides in meningococcal meningitis and septicaemia must surely have been one of the most dramatic events in modern medicine, and their value was fully documented soon after they were introduced. The honeymoon was a long one, lasting from the late 1930s until 1963 when the emergence of sulphonamide resistance made it impossible to use these agents in meningitis unless the sensitivity pattern was known. Fortunately Neisseria meningitidis remains fully susceptible to penicillin, although it appears to be capable of acquiring a plasmid conferring penicillinase production. For Haemophilus influenzae many antibiotic choices were formerly available, of which ampicillin and chloramphenicol were most widely used until 1974 when resistance to the former drug emerged with its acquisition of the TEM-1 plasmid conferring the capacity for penicillinase production. 01954701/88/02A135
0 1988 The Hospital
+07 $03.00/O
135
Infectmn
Soarty
136
H. P. Lambert
The enormous value of chloramphenicol in this form of meningitis is now threatened by the presence, so far rare, of chloramphenicol-resistant strains. Some of these strains are also penicillinase producers. Where such strains exist, it is now necessary to use extended spectrum cephalosporins, which are of proven value in haemophilus meningitis but which are expensive and require intravenous infusion for the whole treatment period. As with all other examples of antibiotic resistance frequency varies greatly. The course of resistance in H. infEuenzae has been fully documented in the UK over a number of years, and is summarized in Table I. Ampicillin resistance, unknown in 1973, rose from 1.6% in the 1977 survey to 6.2% in the 1981 survey, thereafter remaining at a similar level, 7.8% most recently (Powell et al., 1987). The problem of pneumococcal resistance will be discussed later, in the context of respiratory infections. Although most strains are fully penicillin-susceptible, resistant strains of both types have been isolated in widely scattered locations since the first description of low level penicillin resistance in Papua-New Guinea, and of high level resistance to many antibiotics in South Africa (Appelbaum et al., 1977). Antibiotic resistance problems in meningitis apply not only to the three main organisms, but also to other forms of meningitis. The march of drug resistance in enterobacteria is especially relevant, because of the importance meningitis and in of these organisms as a cause of neonatal immunosuppressed subjects. As with H. influenzae, the extended spectrum cephalosporins are now often called upon. The serious implications of these changes in resistance for the treatment of meningitis, in countries with limited health budgets, is shown by the cost comparisons in Table II. Gastrointestinal
infections
The vast bacterial population of the gut and the ease with which bacteria spread by faecal-oral transmission make the gastrointestinal tract a prime site for the emergence of antibiotic resistance, and there is much evidence to link the level of usage of antibiotics with changes in resistance of the enteric flora (Farrar, 1985). These changes have important effects in two main classes of infection, those affecting the gastrointestinal tract itself, and those at other sites, e.g., urinary tract and peritoneum, caused by organisms of gut Table % Resistant
to
1973 1977 1981 1987 (Adapted from Williams
I. Antibiotic
resistance
Ampicillin 01.6
and Moosden,
of Haemophilus
Chloramphenicol 0 0.2 1.03 1.7
influenzae Tetracycline 102.7 3.1 2.7
1986, and Powell et OZ., 1987).
in UK Trimethoprim i.2 1.4 4.2
Clinical
impact
of drug
137
resistance
II. Approximate cost of 5 days’ treatment in dosage appro *ia@ for meningitis, Pounds ss Grling, 1987
Table
Antibiotic Benzyl penicillin Chloramphenicol Cefuroxime Cefotaxime Ceftazidime Co-trimoxazole
cost 345 9-90 158 193 396 35-10
origin. Because gooclr medical practice rightly discourages the use of antibiotics in the ordinary varieties of acute gastroenteritis, it is easy to forget that antibiotics have a valid, and in some cases a life-saving role in several types of gut infection. These include acute shigellosis and systemic salmonella infections, especially typhoid and paratyphoid, and to a lesser extent cholera and cholera contacts. The spread of antibiotic resistance, mostly plasmid-mediated, has led to very serious diminution of the options available for all these conditions, especially as multiple antibiotic resistance is common in these organisms. Severe shigellosis, for example, has been treated successfully with appropriate antibiotics for many years, but the resistance problem, at its worst, entails a loss of virtually all potential treatments for this serious disease. Shahid et al. (1985) found that nearly all isolates of Shigdu dysenteriae were multiply-resistant, most commonly to streptomycin, tetracycline, chloramphenicol and co-trimoxazole. The emergence of resistance to the latter combination was associated with a vast increase of its use in the population concerned, in recent years. As with other examples, there is wide variation in different populations; in the survey by Murray (1986) the proportion of shigella strains susceptible to ampicillin varied between 7 and 87%, to tetracycline between 11 and 91%, and to co-trimoxazole between 6 and 55%. The use of nalidixic acid and its congeners has been much discussed recently, and one especial advantage claimed for these agents is the apparent absence of transmissible drug resistance associated with their use. Unfortunately, plasmid-mediated resistance to nalidixic acid in S. dysenteriae type 1 has recently been reported from Bangladesh, and the number of isolates with this character is rapidly increasing (Munshi et al., 1987). Antibiotics have been employed in cholera with two main functions. First, an appropriate agent significantly reduces the requirement of replacement fluid and second, treatment of household contacts reduces their likelihood of developing the illness. Both these possible uses have been greatly impeded by rapid emergence of multiple resistance. For example, Mhalu et al. (1979) documented this process during the first 6 months of an epidemic in .Tanzania. Tetracycline was used extensively in treatment and
138
H. P. Lambert
prophylaxis, and, whereas early isolates had been fully drug-susceptible, towards the end of the period 76% of them were resistant to tetracycline and also in many cases to numerous other agents. In typhoid, drug resistance has not so far become as pressing a problem as in other bowel infections. Although resistance to chloramphenicol and to trimethoprim is well documented in many areas of the world, its frequency has so far not been great enough to impose major constraints in treatment. The situation is very different in non-typhoid salmonellae, in which multiple drug resistance is extremely common. The pathway of resistant strains from animal sources of salmonella into human populations has frequently been demonstrated; a particularly clear-cut example can be seen in the case of trimethoprim, since the increased frequency of resistance in strains of human origin followed the trend in strains from cattle (Ward et al., 1982). Other outbreaks of salmonellosis with multiple-resistant strains are, however, associated with human-to-human spread. The clinical significance of these events is that, although antibiotics are not indicated in salmonella gastroenteritis, invasive infections are not uncommon and require antibiotic treatment. The role of antibiotics in travellers’ diarrhoea has been in dispute for many years. It is sad, therefore, that so soon after evidence of modest benefits have been demonstrated for drugs like co-trimoxazole and doxycycline, their value should rapidly have been vitiated by the spread of drug resistance in Escherichia coli strains of bowel origin. The wide variation in resistance patterns already mentioned makes it impossible to predict what benefit might be gained by a traveller to an area in which no recent epidemiological evidence is available. One can only speculate that countries, over-the-counter where, as is common in developing antimicrobials are easily available, the possible benefits of antimicrobial agents either in prevention or treatment of travellers’ diarrhoea are likely to be nullified.
Respiratory
infections
The impact of drug resistance is especially difficult to assess in this vast and important group of infections because their aetiological diversity, and the difficulties in attributing syndromes to particular causal agents makes for much confusion. Nevertheless, such recent studies as there are tend to support older work suggesting that Streptococcus pneumoniae retains its dominance as a cause of bacterial pneumonia of non-hospital origins at all ages and that, in developing countries, this organism and H. influenzae are the dominant causes of childhood pneumonia. The development of resistance in H. injhenzae has already been fully discussed, but a little more must be said about the pneumococcus. Although resistance is still relatively uncommon, it is disturbing that resistant strains have now been reported from a great variety of locations,
Clinical
impact
of drug resistance
139
and that in many countries it is no longer safe to assume full penicillin-susceptibility in this important organism. In some countries the situation is worse, and penicillin-resistant strains are already established as an important component of the pneumococcal population. As to the problem of how penicillin-insensitivity affects treatment in pneumococcal pneumonia, a useful contribution has recently been made by workers in Spain (Pallares et al., 1987), one of the countries in which pneumoccocal resistance is reaching serious proportions. They studied 24 adults with bacteraemic pneumococcal pneumonia, reaching the conclusion that high dose penicillin was probably effective when the causal strain showed moderate resistance (i.e., MIC 2 g 1-l) but not if the resistance level was high. Alarming features of their study included the findings that 35 of 306 (ll%)ofbl oo d isolates of pneumococcus were penicillin-resistant, and that, of healthy children in Barcelona with nasal carriage of pneumococci, 33% of the isolates showed moderate resistance and 3% were highly resistant. Are we perhaps seeing the end of the penicillin era for pneumococcal infection? In nosocomial pneumonia we have to contend, in addition, with Enterobacteriaceae, pseudomonads and Staphylococcus aureus, all of them notable for their tendency to produce drug-resistant strains. The problems raised by these organisms are dealt with fully elsewhere in this Symposium. Returning to the community, it is important to remember that S. pneumoniae and H. injluenzae are the important pathogens in otitis media and acute sinusitis, and treatment of these conditions is rendered more difficult as resistant strains emerge. It is lucky that Streptococcus pyogenes has remained fully penicillin-susceptible but resistance to tetracycline and to macrolides is common and its frequency closely related to the level of use of these compounds. Sexually
transmitted
diseases
The development of drug resistance in the gonococcus has been documented in massive detail over many years. By the late 1940s sulphonamides were no longer effective because of drug resistance and at about the same time progressive increase of penicillin resistance associated with chromosomal mutations was first observed. Success of treatment in gonorrhoea and MIC against the infecting strain show a close inverse correlation and, as the years passed, the dose of penicillin necessary to achieve a cure rose progressively, reaching 4.8 mega-units with the additional use of probenecid. In 1975 the situation changed again with the emergence of penicillinase-producing Neisseria gonorrhoeae (PPNG), at first in the Far East and in West Africa, then rapidly in many other countries, and these strains are now world wide. Most authorities agree that penicillin-based regimens have to be abandoned if the incidence of PPNG in gonococcal isolates rises much above 1%. The problem of antibiotic resistance in non-PPNG strains is also of great
140
H. P. Lambert
importance. Many strains also show high levels of resistance to tetracycline, erythromycin and chloramphenicol and Brown et al. (1982) describing the characteristics of such strains in Bangkok added a question to the title of their paper, ‘is single-drug treatment passe’?. Non-PPNG strains have been described in the US which are totally penicillin-resistant. Another recent addition to the varieties of antibiotic resistance in gonococci is the emergence of plasmid-mediated tetracycline resistance, a serious limitation where this drug is used for presumed dual infection with gonorrhoea and chlamydia. These patterns of drug resistance in gonococci have imposed serious limitations in treatment and have necessitated progressive changes in clinic practice often to less convenient and more expensive regimens. In areas where PPNG are prevalent, WHO-approved treatment schemes include spectinomycin, ceftriaxone, cefotaxime and cefoxitin, while less expensive regimens effective in some areas include kanamycin, thiamphenicol and co-trimoxazole. The world picture of gonococcal drug resistance and its implications for treatment are well described in a review by Meheus (1987). Conclusion
Ample evidence is available of the ways in which antibiotic resistance has imposed serious limitations on the treatment of most important bacterial infections. Although in most cases other drugs are available which can be substituted for those lost by the emergence of resistance, the alternative drug is often less desirable for various reasons; its efficacy may be less well proven, it may have greater toxicity, or be more expensive. Of the difficulties facing us at present in relation to infections of community origin, perhaps the most threatening are those presented by the possible increase of chloramphenicol resistance in serious infections caused by H. injluenzae, by multiple drug resistance in bacterial gut infections especially shigellosis and by the real possibility of more widespread penicillin resistance in pneumococci. The attention of interested readers is drawn to the report of a study of this problem carried out between 1983 and 1986, sponsored by the Fogarty International Centre (Levy et al., 1987). References Appelbaum, P. C., Bhamjee, A., Scragg, J. N., Hallett, A. F., Bowen, A. J. & Cooper, R. C. (1977). Streptococcus pneumoniae resistant to penicillin and chloramphenicol. Lancet ii, 192-195. Brown, S., Warnnissorn, T., Biddle, J., Panikabutra, K. Sz Traisura, A. (1982). Antimicrobial resistance of N. gonorrhoeae in Bangkok; is single-drug treatment passe. Lancet ii, 13661368. Farrar, W. E. (1985). Antibiotic resistance in developing countries. Journal of. Infectious Diseases 152, 1103-I 106. Levy, S. B., Burke, J. P. & Wallace, C. K., Eds (1987). Antibiotic use and antibiotic resistance worldwide. Reviews of Infectious Diseases 9, 5231-5316.
Clinical
impact
of drug
resistance
141
Meheus, A. (1987). Gonorrhoea. In Sexually Transmitted Diseases in the Tropics (Osoba, A.-O., Ed.), pp. 17-31. Clinical Tropical Medicine and Communicable Disease, Vol. 2, No. 1. Ball&e Tindall, London. Mhalu, F. S., Mmari, P. W. & Ijumba, J. (1979). Rapid emergence of El Tor Vibrio cholerae resistant to antimicrobial agents during first six months of 4th cholera epidemic in Tanzania. Lancet i, 345-347. Munshi, M. H., Salk, D. A., Haider, K., Ahmed, 2. U., Rahaman, M. M. & Morshed, M. G. (1987). Plasmid-mediated resistance to nalidixic acid in Shigella dysenteriae Type 1. Lancet ii, 419421. Murray, B. E. (1986). Resistance of Shigella, Salmonella and other selected enteric pathogens to antimicrobial agents. Reviews of Infectious Diseases 8, S172-S181. Pallares, R., Gudiol, F., Linares, J., Ariza, J., Rufi, G., Murgui, L., Dorca, J. & Viladrich, P. F. (1987). Risk factors and response to antibiotic therapy in adults with bacteraemic pneumoniae caused by penicillin-resistant pneumococci. New England Journal of Medicine 317, 18-22. Powell, M., Koutsia-Carouzou, C., Voutsinas, D., Seymour, A. & Williams, J, D. (1987). Resistance of clinical isolates of Haemophilus z’nfluenzae in United Kingdom 1986. British Medical Journal 295, 176-l 79. Shahid, N. S., Rahaman, M. M., Haider, K., Banu, H. & Rahman, N. (1985). Changing pattern of resistant Shiga bacillus (Shigella dysenteriae type 1) and Shigella j?exneri in Bangladesh. Journal of Infectious Diseases 152, 11141119. Ward, L. R., Rowe, B. & Threlfall, E. J. (1982). Incidence of trimethoprim resistance in Salmonellae isolated in Britain: a twelve vear studv. Lancet ii, 705-706. Williams, J. D. & Moosden, F. (1986). Antibiotic resistance in.IIaemophilus influenzae. Epidemiology, mechanisms and therapeutic possibilities. Reviews of Infectious Diseases 8, SSSS-561.
of Hospital Infection (1988) 11 (Supplement
Clinical
imp$acf
A), 135-141
of drug
resistance
H. P. Lambert Department
of Communicable Diseases, St. George’s Hospital Cranmer Terrace, London S WI 7 ORE
Medical
School,
Introduction Other papers in this Symposium deal with the mechanisms of drug resistance and with the problems of its control. I confine this discussion to an account of the ways in which the spread of resistant organisms has acted as a constraint by limiting, or in some cases totally abrogating, the use of particular agents in prophylaxis and therapy. The very diverse time scale of antibiotic resistance problems makes it necessary to examine changing patterns of usage over a period of several decades. Traditionally community-acquired and hospital-acquired infections are considered separately, but ample epidemiological evidence now testifies to the ease with which bacterial populations in the community and hospital interact. It is, nevertheless, convenient to deal with the two main epidemiological groupings separately and, because so much of the Conference is concerned with hospital infection, the main emphasis here will be on infections arising in the community. Meningitis The use of sulphonamides in meningococcal meningitis and septicaemia must surely have been one of the most dramatic events in modern medicine, and their value was fully documented soon after they were introduced. The honeymoon was a long one, lasting from the late 1930s until 1963 when the emergence of sulphonamide resistance made it impossible to use these agents in meningitis unless the sensitivity pattern was known. Fortunately Neisseria meningitidis remains fully susceptible to penicillin, although it appears to be capable of acquiring a plasmid conferring penicillinase production. For Haemophilus influenzae many antibiotic choices were formerly available, of which ampicillin and chloramphenicol were most widely used until 1974 when resistance to the former drug emerged with its acquisition of the TEM-1 plasmid conferring the capacity for penicillinase production. 01954701/88/02A135
0 1988 The Hospital
+07 $03.00/O
135
Infectmn
Soarty
136
H. P. Lambert
The enormous value of chloramphenicol in this form of meningitis is now threatened by the presence, so far rare, of chloramphenicol-resistant strains. Some of these strains are also penicillinase producers. Where such strains exist, it is now necessary to use extended spectrum cephalosporins, which are of proven value in haemophilus meningitis but which are expensive and require intravenous infusion for the whole treatment period. As with all other examples of antibiotic resistance frequency varies greatly. The course of resistance in H. infEuenzae has been fully documented in the UK over a number of years, and is summarized in Table I. Ampicillin resistance, unknown in 1973, rose from 1.6% in the 1977 survey to 6.2% in the 1981 survey, thereafter remaining at a similar level, 7.8% most recently (Powell et al., 1987). The problem of pneumococcal resistance will be discussed later, in the context of respiratory infections. Although most strains are fully penicillin-susceptible, resistant strains of both types have been isolated in widely scattered locations since the first description of low level penicillin resistance in Papua-New Guinea, and of high level resistance to many antibiotics in South Africa (Appelbaum et al., 1977). Antibiotic resistance problems in meningitis apply not only to the three main organisms, but also to other forms of meningitis. The march of drug resistance in enterobacteria is especially relevant, because of the importance meningitis and in of these organisms as a cause of neonatal immunosuppressed subjects. As with H. influenzae, the extended spectrum cephalosporins are now often called upon. The serious implications of these changes in resistance for the treatment of meningitis, in countries with limited health budgets, is shown by the cost comparisons in Table II. Gastrointestinal
infections
The vast bacterial population of the gut and the ease with which bacteria spread by faecal-oral transmission make the gastrointestinal tract a prime site for the emergence of antibiotic resistance, and there is much evidence to link the level of usage of antibiotics with changes in resistance of the enteric flora (Farrar, 1985). These changes have important effects in two main classes of infection, those affecting the gastrointestinal tract itself, and those at other sites, e.g., urinary tract and peritoneum, caused by organisms of gut Table % Resistant
to
1973 1977 1981 1987 (Adapted from Williams
I. Antibiotic
resistance
Ampicillin 01.6
and Moosden,
of Haemophilus
Chloramphenicol 0 0.2 1.03 1.7
influenzae Tetracycline 102.7 3.1 2.7
1986, and Powell et OZ., 1987).
in UK Trimethoprim i.2 1.4 4.2
Clinical
impact
of drug
137
resistance
II. Approximate cost of 5 days’ treatment in dosage appro *ia@ for meningitis, Pounds ss Grling, 1987
Table
Antibiotic Benzyl penicillin Chloramphenicol Cefuroxime Cefotaxime Ceftazidime Co-trimoxazole
cost 345 9-90 158 193 396 35-10
origin. Because gooclr medical practice rightly discourages the use of antibiotics in the ordinary varieties of acute gastroenteritis, it is easy to forget that antibiotics have a valid, and in some cases a life-saving role in several types of gut infection. These include acute shigellosis and systemic salmonella infections, especially typhoid and paratyphoid, and to a lesser extent cholera and cholera contacts. The spread of antibiotic resistance, mostly plasmid-mediated, has led to very serious diminution of the options available for all these conditions, especially as multiple antibiotic resistance is common in these organisms. Severe shigellosis, for example, has been treated successfully with appropriate antibiotics for many years, but the resistance problem, at its worst, entails a loss of virtually all potential treatments for this serious disease. Shahid et al. (1985) found that nearly all isolates of Shigdu dysenteriae were multiply-resistant, most commonly to streptomycin, tetracycline, chloramphenicol and co-trimoxazole. The emergence of resistance to the latter combination was associated with a vast increase of its use in the population concerned, in recent years. As with other examples, there is wide variation in different populations; in the survey by Murray (1986) the proportion of shigella strains susceptible to ampicillin varied between 7 and 87%, to tetracycline between 11 and 91%, and to co-trimoxazole between 6 and 55%. The use of nalidixic acid and its congeners has been much discussed recently, and one especial advantage claimed for these agents is the apparent absence of transmissible drug resistance associated with their use. Unfortunately, plasmid-mediated resistance to nalidixic acid in S. dysenteriae type 1 has recently been reported from Bangladesh, and the number of isolates with this character is rapidly increasing (Munshi et al., 1987). Antibiotics have been employed in cholera with two main functions. First, an appropriate agent significantly reduces the requirement of replacement fluid and second, treatment of household contacts reduces their likelihood of developing the illness. Both these possible uses have been greatly impeded by rapid emergence of multiple resistance. For example, Mhalu et al. (1979) documented this process during the first 6 months of an epidemic in .Tanzania. Tetracycline was used extensively in treatment and
138
H. P. Lambert
prophylaxis, and, whereas early isolates had been fully drug-susceptible, towards the end of the period 76% of them were resistant to tetracycline and also in many cases to numerous other agents. In typhoid, drug resistance has not so far become as pressing a problem as in other bowel infections. Although resistance to chloramphenicol and to trimethoprim is well documented in many areas of the world, its frequency has so far not been great enough to impose major constraints in treatment. The situation is very different in non-typhoid salmonellae, in which multiple drug resistance is extremely common. The pathway of resistant strains from animal sources of salmonella into human populations has frequently been demonstrated; a particularly clear-cut example can be seen in the case of trimethoprim, since the increased frequency of resistance in strains of human origin followed the trend in strains from cattle (Ward et al., 1982). Other outbreaks of salmonellosis with multiple-resistant strains are, however, associated with human-to-human spread. The clinical significance of these events is that, although antibiotics are not indicated in salmonella gastroenteritis, invasive infections are not uncommon and require antibiotic treatment. The role of antibiotics in travellers’ diarrhoea has been in dispute for many years. It is sad, therefore, that so soon after evidence of modest benefits have been demonstrated for drugs like co-trimoxazole and doxycycline, their value should rapidly have been vitiated by the spread of drug resistance in Escherichia coli strains of bowel origin. The wide variation in resistance patterns already mentioned makes it impossible to predict what benefit might be gained by a traveller to an area in which no recent epidemiological evidence is available. One can only speculate that countries, over-the-counter where, as is common in developing antimicrobials are easily available, the possible benefits of antimicrobial agents either in prevention or treatment of travellers’ diarrhoea are likely to be nullified.
Respiratory
infections
The impact of drug resistance is especially difficult to assess in this vast and important group of infections because their aetiological diversity, and the difficulties in attributing syndromes to particular causal agents makes for much confusion. Nevertheless, such recent studies as there are tend to support older work suggesting that Streptococcus pneumoniae retains its dominance as a cause of bacterial pneumonia of non-hospital origins at all ages and that, in developing countries, this organism and H. influenzae are the dominant causes of childhood pneumonia. The development of resistance in H. injhenzae has already been fully discussed, but a little more must be said about the pneumococcus. Although resistance is still relatively uncommon, it is disturbing that resistant strains have now been reported from a great variety of locations,
Clinical
impact
of drug resistance
139
and that in many countries it is no longer safe to assume full penicillin-susceptibility in this important organism. In some countries the situation is worse, and penicillin-resistant strains are already established as an important component of the pneumococcal population. As to the problem of how penicillin-insensitivity affects treatment in pneumococcal pneumonia, a useful contribution has recently been made by workers in Spain (Pallares et al., 1987), one of the countries in which pneumoccocal resistance is reaching serious proportions. They studied 24 adults with bacteraemic pneumococcal pneumonia, reaching the conclusion that high dose penicillin was probably effective when the causal strain showed moderate resistance (i.e., MIC 2 g 1-l) but not if the resistance level was high. Alarming features of their study included the findings that 35 of 306 (ll%)ofbl oo d isolates of pneumococcus were penicillin-resistant, and that, of healthy children in Barcelona with nasal carriage of pneumococci, 33% of the isolates showed moderate resistance and 3% were highly resistant. Are we perhaps seeing the end of the penicillin era for pneumococcal infection? In nosocomial pneumonia we have to contend, in addition, with Enterobacteriaceae, pseudomonads and Staphylococcus aureus, all of them notable for their tendency to produce drug-resistant strains. The problems raised by these organisms are dealt with fully elsewhere in this Symposium. Returning to the community, it is important to remember that S. pneumoniae and H. injluenzae are the important pathogens in otitis media and acute sinusitis, and treatment of these conditions is rendered more difficult as resistant strains emerge. It is lucky that Streptococcus pyogenes has remained fully penicillin-susceptible but resistance to tetracycline and to macrolides is common and its frequency closely related to the level of use of these compounds. Sexually
transmitted
diseases
The development of drug resistance in the gonococcus has been documented in massive detail over many years. By the late 1940s sulphonamides were no longer effective because of drug resistance and at about the same time progressive increase of penicillin resistance associated with chromosomal mutations was first observed. Success of treatment in gonorrhoea and MIC against the infecting strain show a close inverse correlation and, as the years passed, the dose of penicillin necessary to achieve a cure rose progressively, reaching 4.8 mega-units with the additional use of probenecid. In 1975 the situation changed again with the emergence of penicillinase-producing Neisseria gonorrhoeae (PPNG), at first in the Far East and in West Africa, then rapidly in many other countries, and these strains are now world wide. Most authorities agree that penicillin-based regimens have to be abandoned if the incidence of PPNG in gonococcal isolates rises much above 1%. The problem of antibiotic resistance in non-PPNG strains is also of great
140
H. P. Lambert
importance. Many strains also show high levels of resistance to tetracycline, erythromycin and chloramphenicol and Brown et al. (1982) describing the characteristics of such strains in Bangkok added a question to the title of their paper, ‘is single-drug treatment passe’?. Non-PPNG strains have been described in the US which are totally penicillin-resistant. Another recent addition to the varieties of antibiotic resistance in gonococci is the emergence of plasmid-mediated tetracycline resistance, a serious limitation where this drug is used for presumed dual infection with gonorrhoea and chlamydia. These patterns of drug resistance in gonococci have imposed serious limitations in treatment and have necessitated progressive changes in clinic practice often to less convenient and more expensive regimens. In areas where PPNG are prevalent, WHO-approved treatment schemes include spectinomycin, ceftriaxone, cefotaxime and cefoxitin, while less expensive regimens effective in some areas include kanamycin, thiamphenicol and co-trimoxazole. The world picture of gonococcal drug resistance and its implications for treatment are well described in a review by Meheus (1987). Conclusion
Ample evidence is available of the ways in which antibiotic resistance has imposed serious limitations on the treatment of most important bacterial infections. Although in most cases other drugs are available which can be substituted for those lost by the emergence of resistance, the alternative drug is often less desirable for various reasons; its efficacy may be less well proven, it may have greater toxicity, or be more expensive. Of the difficulties facing us at present in relation to infections of community origin, perhaps the most threatening are those presented by the possible increase of chloramphenicol resistance in serious infections caused by H. injluenzae, by multiple drug resistance in bacterial gut infections especially shigellosis and by the real possibility of more widespread penicillin resistance in pneumococci. The attention of interested readers is drawn to the report of a study of this problem carried out between 1983 and 1986, sponsored by the Fogarty International Centre (Levy et al., 1987). References Appelbaum, P. C., Bhamjee, A., Scragg, J. N., Hallett, A. F., Bowen, A. J. & Cooper, R. C. (1977). Streptococcus pneumoniae resistant to penicillin and chloramphenicol. Lancet ii, 192-195. Brown, S., Warnnissorn, T., Biddle, J., Panikabutra, K. Sz Traisura, A. (1982). Antimicrobial resistance of N. gonorrhoeae in Bangkok; is single-drug treatment passe. Lancet ii, 13661368. Farrar, W. E. (1985). Antibiotic resistance in developing countries. Journal of. Infectious Diseases 152, 1103-I 106. Levy, S. B., Burke, J. P. & Wallace, C. K., Eds (1987). Antibiotic use and antibiotic resistance worldwide. Reviews of Infectious Diseases 9, 5231-5316.
Clinical
impact
of drug
resistance
141
Meheus, A. (1987). Gonorrhoea. In Sexually Transmitted Diseases in the Tropics (Osoba, A.-O., Ed.), pp. 17-31. Clinical Tropical Medicine and Communicable Disease, Vol. 2, No. 1. Ball&e Tindall, London. Mhalu, F. S., Mmari, P. W. & Ijumba, J. (1979). Rapid emergence of El Tor Vibrio cholerae resistant to antimicrobial agents during first six months of 4th cholera epidemic in Tanzania. Lancet i, 345-347. Munshi, M. H., Salk, D. A., Haider, K., Ahmed, 2. U., Rahaman, M. M. & Morshed, M. G. (1987). Plasmid-mediated resistance to nalidixic acid in Shigella dysenteriae Type 1. Lancet ii, 419421. Murray, B. E. (1986). Resistance of Shigella, Salmonella and other selected enteric pathogens to antimicrobial agents. Reviews of Infectious Diseases 8, S172-S181. Pallares, R., Gudiol, F., Linares, J., Ariza, J., Rufi, G., Murgui, L., Dorca, J. & Viladrich, P. F. (1987). Risk factors and response to antibiotic therapy in adults with bacteraemic pneumoniae caused by penicillin-resistant pneumococci. New England Journal of Medicine 317, 18-22. Powell, M., Koutsia-Carouzou, C., Voutsinas, D., Seymour, A. & Williams, J, D. (1987). Resistance of clinical isolates of Haemophilus z’nfluenzae in United Kingdom 1986. British Medical Journal 295, 176-l 79. Shahid, N. S., Rahaman, M. M., Haider, K., Banu, H. & Rahman, N. (1985). Changing pattern of resistant Shiga bacillus (Shigella dysenteriae type 1) and Shigella j?exneri in Bangladesh. Journal of Infectious Diseases 152, 11141119. Ward, L. R., Rowe, B. & Threlfall, E. J. (1982). Incidence of trimethoprim resistance in Salmonellae isolated in Britain: a twelve vear studv. Lancet ii, 705-706. Williams, J. D. & Moosden, F. (1986). Antibiotic resistance in.IIaemophilus influenzae. Epidemiology, mechanisms and therapeutic possibilities. Reviews of Infectious Diseases 8, SSSS-561.