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Microbiology of acute otitis media and therapeutic consequences
INTERNATIONAL IOIJRllAL OF
PediJ!ric
ELSE VIER
International Journal of Pediatric Otorhinolaryngology 32 (Suppl.) (1995) S145-S156
uto Rhino Laryngology
Symposium
Microbiology of acute otitis media and therapeutic consequences Karin Prellner*a (Chairman), Gunnar Kahlmeter b , Paola Marchisioc , Paul B. van Cauwenberged "Dept of Otorhinolaryngology, University Ho;,piWI, S-221 85 Lund, S.\'eden hDepartment of Clinical Microbiology, Central Hospital, ViixjO, Sweden 'Pediatric Dept, University of Milan, Milan, Italy "Dept of Otorhinolaryngology, University of Ghent, Ghent, Belgium
1. Introduction 'In 1992, 13,300 hospital patients died of infections that resisted every drug doctors tried' according to Newsweek (28 March 1994). Although this sentence did not allude to infections emerging from the upper respiratory tract, we are now facing a huge problem concerning increasing resistance to antimicrobial drugs among bacteria associated with acute purulent otitis media (AOM). Fig. I illustrates how the problem is escalating. It is obvious that new strategies for the use of antimicrobials are necessary. Before dealing with this question we will give background data and try to answer the central questions (I - IV) addressed in this symposium. 2. Question I: What is the clinical significance of various bacteria?
2.1. Therapeutic failures It is well known that the symptoms of AOM sometimes persist or recur during antibiotic therapy. However, the extent of such failure is still incompletely known, as is the cause of therapeutic failure, which has - apart from non-compliance been supposed to be due mainly to infection with microorganisms resistant to the drug used. In this respect interest has until recently focused on f3-lactamase-producing Haemophilus influen::ae and Moraxella catarrhalis.
* Corresponding author.
o165-5876/95/$09.5U
(1995 Elsevier Science Ireland Ltd. All rights reserved SSDI 0 165-5876( 94)0 1152-2
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Use 0/ antibiotics
TIIerfIPeutl.c shift towards broad spectrum (IJId/or
new antibiotics
/ncrusing Incidence 0/IlIIIimJcrobitzJ resislllnce to cllnictdly slgnl./lctllll levels
Fig. I. Escalating problems with use of antibiotics.
In a study of 75 children with therapeutic failures as judged by general practitioners (GP) and referred to an ENT-specialist for careful examination with otomicroscope and sampling of bacterial specimens, only II (15'1.,) fulfilled the criteria for a diagnosis of therapeutic failure, while 85% did not [20]. In 4/11 children no pathogens could be isolated and in the other 7 patients fJ -Iactamasenegative H. influen::ae were found in the middle ear effusion (MEE). Only one child showed growth of a fJ -Iactamase-producing M. catarrhalis, which was found in the nasopharynx (NPH) concomitantly with pure culture of non-fJ-lactamase-producing H. influen::ae in the MEE. In another study [12], 113 children were closely followed for three years from birth. Three hundred episodes of AOM occurred and 22 were instances of failure to respond to the primary antibiotic therapy. The risk of failure did not differ between the various drugs used but was significantly greater (fourfold) during the first year of life than during the following years. MEE/NPH specimens were collected before treatment in 17 of the 22 (77.7%) failures. Only 3 strains were in vitro found to be resistant to the drug used and were fJ-Iactamase-producing. It might be speculated· that one more such strain would have been identified if pretreatment cultures had been taken in all 22 instances. Thus, among 300 AOM episodes fJ-Iactamase-producing strains could have been responsible for the failure in 1.3 per cent (4/300). A similar percentage is obtained by calculation: about 20% of AOM is caused by H. influen::ae and 5%- 10% by M. catarrhalis, of which about 7% and 90%, respectively, produce fJ-Iactamase. Thus, '" 8% of all AOM episodes are due to fJ-Iactamase-producing bacteria. Since healing without treatment occurs in about 75% of AOM, fJ-Iactamase-producing
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bacteria might be suspected to contribute to unfavourable development in approximately 2'X, of AOM episodes. To conclude: the number of cases with therapeutic failure is highly overestimated unless the tympanic membrane is carefully examined, preferably by otomicroscopy. Being less than 1 year old constitutes a major risk factor for failure. In vitro testing of drug resistance in young children seems to have low predictive value. Although j3-lactamase-producing bacteria may cause failure during therapy of AOM [4,12,21,35], the results indicate that such bacteria might not be of major clinical importance. 2.2. Complications in A 0 M Acute mastoiditis is most common in children below 2 years. The incidence requiring operation declined steeply after the introduction of antimicrobial agents such as sulphonamide and penicillin G. A further decrease in the incidence has occurred during the past three decades [28]. However, the proportion of more serious complications (meningitis, epidural abscess, sepsis, death) to acute mastoiditis does not seem to have decreased [10,38]. What is then our knowledge concerning bacteria in conjunction with acute mastoiditis? In 29 children, median age 13 months, with clinical signs of acute mastoiditis and in whom mastoid ectomy and myringotomy were undertaken between 1970 and 1989, bacteriological examinations were performed [31]. With the exception that no strain of M. catarrhalis was found, different results were obtained when analysing the children with (n = IS) and without (n = 14) antibiotic treatment prior to admission (Table I). In the patients without antibiotic pre-treatment, pneumococci or j3-hemolytic streptococci were isolated in 10/14 cases. No isolates of H. injluenzae were found (Table I). As illustrated in Table I, pneumococci and j3 -hemolytic streptococci are the major pathogens in acute mastoiditis [9,10,13,14,25,27,28,34]. H. injluenzae is an infrequent finding and no strain has been reported to produce j3-lactamase. In the
Table 1 Reported bacteriological findings in acute mastoiditis (,1.,) Reference
Period
Beta-hemolytic streptococci
Pneumococci
[27] [10] [28] [ 13]
1954-1958 1955-1980 1974-1982 1972-1982
31 16 8 44
13 29 42 33
4 2 8 0
[31], [32]
1970-1984 Without abo With abo
9 18 0
36 54 18
14 0 28
H. influen:ae
No pathogens 27 20 25 Only those with positive culture were included 23 0 45
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few studies where capsulation was looked for, the H. influenzae strains were found to be encapsulated (type b) [10,25,26,28]. M. catarrhalis was not found in any of the studies. In the literature only one case report was found - in non-immunocompromised host - where an invasive infection in connection with otitis media might have been caused by a Moraxella strain. To conclude: pneumococci and f3-hemolytic streptococci are by far the most important bacteria concerning risk for complications. Based on present knowledge - including experimental otitis media studies [22] - it could be doubted whether unencapsulated H. injluenzae or M. catarrhalis have to be feared in the context of serious complications to AOM. 3. Questions II, III. Antimicrobial resistance in bacteria causing acute otitis media Streptococcus pneumoniae, Haemophilus injluenzae and Moraxella catarrhalis cause more than 90% of all AOM episodes. In each of these species, major resistance development to clinically useful antimicrobial agents has occurred over the past 20 years. In some parts of the world antimicrobial resistance development has reached proportions where the choice of antimicrobial therapy is severely restricted and where public media have started to take notice (Newsweek. 28 March 1994). Streptococcus pneumoniae that are inhibited by benzylpenicillin concentrations of ~ 0.1 mg/I are internationally considered susceptible and clinically available with standard f3 -Iactam dosages. Strains requiring ;;:: 2.0 mg/I are considered resistant and not therapeutically available with f3-lactam drugs. Significant penicillin resistance in S. pneumoniae was reported from South Africa in 1977 by Appelbaum and co-workers [1]. and shortly after multiply drug resistant S. pneumoniae were isolated by Jacobs et al. [16]. In South Africa the incidence of penicillin resistance has increased from approximately 5% in 1980 to 15% in 1990 [19]. The mechanism for penicillin resistance, the alteration of an essential penicillin binding protein (PBP2). affects the activity of all f3-lactam drugs including cephalosporins. imipenem and meropenem. Penicillin-resistant S. pneumoniae exhibit minimum inhibitory concentrations (MICs) for cephalosporins, imipenem and meropenem which are clearly higher than those seen in strains susceptible to penicillin (Table 2. compiled from [15]). In severe or complicated infections it is prudent to consider penicillin-resistant S. pneumoniae resistant to all f3-lactam drugs. In S. pneumoniae resistance mechanisms to virtually all clinically useful antimicrobial agents, including new macrolides and quinolones. have now been described. Erythromycin resistance automatically confers resistance to roxithromycin, clarithromycin and azithromycin and resistance to one quinolone would automatically render other quinolones useless. The international magnitude of the problem is shown in Table 3. Local outbreaks with one or more strains exhibiting multiple resistance have occurred in several countries such as South Africa, USA, Spain and Iceland. Hitherto the strains have always been susceptible to vancomycin if nothing else.
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Table 2 S. pneumoniae and betalactam cross resistance (compiled from [15]) Strains classified according to benzylpenicillin MIC (mg/I) Betalactam drug
Susceptible
Intermediate
Resistant
Benzylpenicillin (PeG) Ampicillin Cefaclor Cefotaxime Cefuroxime Ceftazidime Ceftizoxime Cefexime Cefoperazone Cefpirome Imipenem Meropenem
<0.03 <0.03 0.5 <0.06 0.06 0.25 0.5 0.5 0.12 0.01 <0.03 <0.03
0.5-1 0.5-1 32 0.25-0.5 2 32 16 16 1-2 0.5 0.25-1 0.25-1
4-16 8 64 1-4 16 64 32 32 2-8 I 0.5-2 0.5-2
Table 3 Antimicrobial resistance in Streptococcus pneumoniae in various countries in the period 1988- 1992 Country
South Africa Spain France Hungary Iceland USA Sweden UK
Penicillin
Erythromycin
Tetracycline
15'X, 13%
9(1..
I21Y;.
26(!~,
20 11.)
47% 15%
44(~;;1
59%
<1%
6(Yc) 2(1.)
2(X)
3('/0
T'/o
g(Yt)
1(;;.
Trimethoprim sulphamethoxazole
38%
In Haemophilus injluenzae, resistance to penicillins, tetracyclines and chloramphenicol was described in the 1970s. Resistance to trimethoprim - sulphamethoxazole and more recently to quinolones is emerging. There are two completely different mechanisms of penicillin resistance. One is due to the formation of fJ-lactamase mediated by at least two different plasmids of which the TEM-I-plasmid is the most common. The other mechanism is chromosomally mediated and involves alteration of penicillin binding proteins. The activities of various fJ-lactam drugs to strains with penicillin resistance mechanisms are summarized in Table 4. The clinical significance of fi-lactamase production is undisputed whereas the relevance of penicillin resistance in fJ-lactamase-non-producing H. injiuen::ae is unclear [37]. To be conservative such strains should be assumed to be clinically resistant to other fJ-lactam drugs [2].
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Table 4 Antimicrobial activity of betalactam drugs to Haemophilus injluenzae with betalactamase production or chromosomally mediated betalactam resistance Antimicrobial agent
Betalactamase resistance
Chromosomal resistance
Benzylpenicillin (PeG) Phenoxymethylpenicillin (PcV) Ampicillin Ampicillin + c1avulanic acid Cephalosporins Imipenem, Meropenem
No activity No activity No activity Active Active Active
No activity No activity No activity No activity Variable activity Variable activity
H.il'lfluenzae and betalactamase in Europe 1988/89
(compiled from re'entnce18)
!ta!Y Austria Germany (W) United KingdOm Netherlands Belgium Switzerland
!;;;""-----~==l
:
i:: ~b
" k:: I
~==;;;;~~~~__~~~~ o 20 40 60
France Spain II!!
Betalactamase (%)
Fig. 2. H. injluenzae and betalactamase in Europe 1988 - 1989 (compiled from [18]). Table 5 Antimicrobial resistance in Haemophilus injluenzae in various locations in the period 1988 - 1992 Location
Betalactamase resistance
Chromosomal Chloramphenicol penicilIinresistance
Tetracycline
Trimethoprimsulphamethoxazole
USA (1986) Europe (1989) UK Sweden
20'1., 9%
2% 2%
1%
2%
3'0,
5'Yo
0.3u!t, 7%
10%
1%
1%
5% 1%
8%
9(X)
5(X)
Fig. 2 shows the frequency of p-Iactamase-producing H. injluenzae type band non-type b in some European countries (data from [18]). It is evident that p-lactamase production is neither more nor less common in type b strains. Antimicrobial resistance development in H. injluenzae is summarized in Table 5. It is doubtful whether true erythromycin resistance (presence of resistance mechanism) occurs in H. injluenzae. The huge variation in erythromycin resistance
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Table 6 Erythromycin MIC-breakpoints in various countries Country
Regulatory body
Susceptible (mgjl)
Resistant (mgjl)
USA UK France Germany Netherlands Sweden
NCCLS BSAC SFM DIN WRG SRGA
::0;2 ::0; 0.5 ::0;1 ::0;1 ::0;1 ::0; 0.5
:2:8 >0.5 >4 :2:8 :2:4 :2:8
frequencies between countries is above all an expreSSIOn of lack of consensus concerning the MIC-breakpoints (Table 6). In Moraxella catarrhalis the frequency of {3-lactamase-producing strains increased rapidly during the 1980s. {3-lactamase-production is mediated by either of two plasmids, the BRO-l or BRO-2 plasmids, of which the BRO-l is much more common. In Europe ~ 80% of M. catarrhalis produce {3-lactamase [24.30]. The organism is intrinsically resistant to trimethoprim, clindamycin and vancomycin but is often susceptible to sulphamethoxazole, tetracycline and quinolones (resistance < 5'Y.,). In contrast, among the {3-hemolytic group A streptococci, which are the causative agent ill 5%-IO'Yo of AOM, no penicillin-resistant strains have been reported. To conclude: it is necessary to reach a consensus on MIC-breakpoints to facilitate international understanding. The strategies for antimicrobial therapy in AOM must be adapted to local frequencies of antimicrobial resistance. 4. Question IV. Must antibiotics be used at all in treatment and prevention?
4.1. Treatment or no treatment of acute episodes of A 0 M? Since the 1950s the standard treatment of AOM has included antibiotics and analgesics (and sometimes myringotomy). One rationale for this was to decrease the rate of complications. This standard treatment has, however, been questioned during the 1980s [6,7,23]. In the study by Mygind et al. [23] where penicillin V was compared to placebo, 149 children between 1 and 10 years were investigated. Patients were excluded during follow-up 'if complication threatened or another disease required antibiotic treatment'. The results showed satisfactory results in 86% of those treated with penicillin as compared with 69% of those given placebo. The study was rather small and no reliable conclusions vis-a-vis the occurrence of serious complications could be drawn. The authors concluded that an attitude of 'masterly inactivity' regarding antibiotics is justified provided there are reasonable provisions for continued observation of the child. The few studies by other authors in which the effect of antibiotic treatment was compared with that of placebo point in the same direction - some superior effect of antibiotics but high cure rates also on placebo.
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In 1981 van Buchem et al. [6] published the outcome of various 'treatments' in AOM. The objective of the study was to compare the outcome of four different treatment methods: (I) only symptomatic treatment, (2) antibiotics + symptomatic treatment, (3) myringotomy + symptomatic treatment and (4) myringotomy + antibiotics + symptomatic treatment. The study subjects were 171 children, 2 years and older, with 239 affected ears. The diagnosis of AOM was made by a GP and confirmed by an ENT specialist. In only 2 cases was there a disagreement on diagnosis between the ENT specialist and the GP, which is less than I %! The parameters studied were: degree of earache, ear discharge, otoscopic findings, temperature, use of analgesics, relapses, 'irregular course' and complications. The results were rather surprising and gave rise to a lot of discussion in scientific meetings and journals. Indeed, the authors did not find a statistically significant difference between the four treatment groups, except that there were more discharging ears in the myringotomy groups and that the temperature after 24 h was higher in the myringotomy alone group. In the groups treated with antibiotics, the ears discharged for slightly longer and the tympanic membranes took a little longer to heal, but these differences were not significant. There were only four 'irregular courses' and there was no report of mastoiditis or other complications. The authors concluded that symptomatic treatment with vasoconstricting nose drops and analgesics seems to be a reasonable initial approach to AOM in children and that myringotomy and antibiotics can be reserved for cases in which the course of otitis is irregular or if there are complications. Some critical observations on this study included the fact that only children of 2 years and older entered the study, the doubts about accurate diagnosis (AOM or SOM?) and the remark that the series were not large enough to estimate the complication rate. Looking at the diagnostic criteria used and the symptoms of the children included in these studies, they would probably not have been treated by antibiotics in a clinical setting anyway. In another study by van Buchem et al. [7], 4860 children, 2 years and older, with AOM were treated with symptomatic treatment (by GP). They were referred to an ENT specialist in case of an unsatisfactory course. There were only 126 cases (2.7°;;,) with a severe course (1 with mastoiditis); group A streptococci were identified in 30 of them, and H. influen;;;ae only once. Seventy children (1.4'%) had ear discharge lasting longer than 14 days. Since these studies it has become more and more popular, especially among Dutch GPs, not to treat AOM with antibiotics. Today less than 40% of them still give antibiotics in case of AOM in a child older than 2 years. In other parts of the world nearly 100'Y<, of GPs, pediatricians and otolaryngologists give antibiotics. In a more recent study, Kaleida et al. [17] compared the effect of amoxycillin with that of placebo in children with non-severe acute otitis. In the group under the age of 2 years there were no significant differences with regard to the initial treatment failure, the presence of effusion at 6 weeks and the recurrence of AOM; there was, however, a significant difference (P < 0.001) with regard to the presence of an effusion at 2 weeks (52% in the amoxycillin group vs. 68% in the placebo group). For the children older than 2 years, there were no significant differences
K. Prellner el al.j In!. J. Pedialr. Otorhinolaryngol. 32 (Suppl.) (1995) S145-S156
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with regard to the presence of effusion at 6 weeks and the recurrence of AOM, but there were significant differences with regard to the initial treatment failure (0.5'% in the amoxycillin group vs. 5.5% in the placebo group; P = 0.005) and with regard to the presence of effusion at 2 weeks (41 'Yo in the amoxycillin group vs. 56% in the placebo group; P = 0.01). To conclude: there is a need for a careful interpretation of the results without too much extrapolation and always bearing in mind that the physician has to treat individual cases and not trial populations. 4.2. Prevention of recurrent acute otitis media More than 40% of children experience three or more episodes of AOM in the first 3 years of life [36]. Because short- and long-term consequences may have great medical and social impact, prevention is strongly suggested at least in children with recurrent episodes in a short period of time. Among the various approaches - chemoprophylaxis, immunoprophylaxis, surgery and, more recently, control of environmental risk factors - antibiotic prophylaxis is today considered the best medical option. Different schemes of prophylaxis have been used: from sulfonamides given twice daily for 3 months only during the winter season [29] to amoxicillin given once daily for 6 months, irrespective of the season [33]. A recent metanalysis of randomized clinical trials confirmed that all the drugs and all the schemes used for prophylaxis are effective in preventing recurrences [5]. Despite this, many questions regarding the time of beginning, the mode of administration and the duration of prophylaxis remain unsolved. Moreover, still debated are the problem of compliance with a long-term treatment and that of the possible emergence of resistant strains. Prophylaxis' is traditionally given to children who have had three documented episodes of AOM in 6 months or four episodes in 12 months. Recently it was demonstrated that amoxicillin prophylaxis can reduce the risk of further episodes of AOM in children who had their first AOM before the first birthday. This would suggest that in younger children prophylaxis should be initiated after the second episode 'of AOM. Intermittent prophylaxis (given only when the child develops respiratory symptoms) could theoretically be more suitable for children. However, its efficacy has not always been demonstrated to be equivalent to that reported for .continuous prophylaxis [3,32]. Compliance with prophylaxis can be quite different according to the scheme' of antibiotic administration and the socioeconomic status of the child's family [II]. To improve compliance, the use of long-acting antibiotics may be a possibility. Recently azithromycin, a new macrolide with pharmacokinetic characteristics that permit, despite a once a week administration, continuous therapeutic levels in the MEE, has been demonstrated to be as effective as amoxicillin given daily in preventing AOM (Principi et aI., in progress). Antibiotics have been given for periods ranging from 3 months to 2 years and the current recommendation is to give prophylaxis for approximately 6 months, but there are no conclusive data concerning the optimal duration.
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Fortunately, the emergence of resistant bacterial strains possibly causing AOM during antibiotic prophylaxis has not been proved [8,36]. However, conclusive studies regarding possible modifications of bacterial flora present in various body sites are still lacking. To conclude: antibiotic prophylaxis remain the best medical approach to recurrent AOM. However, a lot of problems remain unsolved and further studies are needed to optimize drug administration. 5. Needs and strategies
Although the problems addressed in this symposium focused on AOM, the needs and strategies for the near future must, due to the present situation with fast emergence of multiresistant bacterial strains, also include general recommendations. (1) We need new antimicrobials with truly new modes of action (a new macrolide or cephalosporin does not solve the problem). (2) The use of antimicrobials as growth or yield promo tors in fish and farming industries must now be seriously questioned. (3) Epidemiological national surveillance must be intensified. (4) To facilitate international understanding, a consensus on MIC-breakpoints must be reached. (5) It is necessary to adopt even more stringent criteria for antimicrobial therapy/ prophylaxis. (6) Strategies for antimicrobial therapy must be adapted to local frequencies of antimicrobial resistance and must include a predetermined therapeutic variability to avoid selection of resistant clones. References [I] Appelbaum, P.c.. Bhamjee, A., Scragg, J.N., Hallett, A.F., Bowen, A.J. and Cooper, R.C. (1977) Streptococcus pneumoniae resistant to penicillin and chloramphenicol. Lancet 2, 995-997. [2] Barry, A.L.. Fuchs. P.c. and Pfaller, M.A. (1993) Susceptibilities of p-Iactamase-producing and non producing strains of Haemophilus irif/uenzae to ceftibuten, cefaclor, cefuroxime, cefixime, cefotaxime, and amoxicillin-clavulanic acid. Antimicrob. Agents Chemother. 37, 14-18. [3] Berman, S., Nuss, R., Roark, R., Huber-Navin, C., Grose, K. and Herrera, M. (1992) Effectiveness of continuous vs. intermittent amoxicillin to prevent episodes of otitis media. Pediatr. Infect. Dis. J. 11, 63-67. [4] Bluestone, C.D. (1986) Otitis media and sinusitis in children. Role of Branhamella catarrhalis. Drugs 31 (Suppl. 3), 132-141. [5] Bonati, M., Marchetti, F., Pistotti, V. et al. (1992) Meta-analysis of antimicrobial prophylaxis for recurrent acute otitis media. Clin. Trials and Meta-analysis 28, 39-50. [6] Buchem, F.L. van, Dunk, J.M. and van't Hof, M.A. (1981) Therapy of acute otitis media: myringotomy, antibiotics, or neither? A double-blind study in children. Lancet, 24, Oct., 883-887. [7] Buchem, F.L. van, Peeters, M.F. and van't Hof, M.A. (1985) Acute otitis media: a new treatment strategy. Br. Med. J. 290, 1033-1037. [8] Cassel brant, M.L., Kaleida, P.H., Rockette, H.E., Paradise, J.L., Bluestone, C.D., Kurs-Lasky, M. et al. (1992) Efficacy of antimicrobial prophylaxis and of tympanostomy tube insertion for prevention of recurrent acute otitis media: results of a randomized clinical trial. Pediatr. Infect. Dis. J. 111, 278-286.
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[9] Faye-Lund, H.A. (1989) Acute and latent mastoiditis. J. Laryngol. Otol. 103, 1158-1160. [10] Ginsburg, C.M., Rudoy, R. and Nelson, J.D. (1980) Acute mastoiditis in infants and children. Clin. Pediatr. (Phila.) 19, 549-553. [II] Goldstein, N .A. and Sculerati, N. (1994) Compliance with prophylactic antibiotics for otitis media in a New York City clinic. Int. J. Pediatr. Otorhinolaryngol. 28, 129-140. [12] Harsten, G., Prellner, K., Heldrup, J., Kalm, O. and Komfiilt, R. (1989) Treatment failure in acute otitis media. A clinical study of children during their first three years of life. Acta Otolaryngol. (Stockh.) 108, 253-258. [13] Hawkins, D., Dru, D., House, l.W. and Clark, R.W. (1983) Acute mastoiditis in children: a review of 54 cases. Laryngoscope 93, 568-572. [14] Hawkins, D.B. and Dru, D. (1983) Mastoid subperiosteal abscess. Arch. Otolaryngol. 109, 369-371. [15] Jacobs, M.R. ( 1992) Treatment and diagnosis of infections caused by drug-resistant Streptococcus pneumoniae. Clin. Infect. Dis. 15, 119-27. [16] Jacobs, M.R., Koomhof, H.J. and Robins-Browne, R.M. (1978) Emergence of multiply resistant pneumococci. N. Engl. J. Med. 299, 735-740. [17] Kaleida, P.H., Cassel brant, M.L., Rockette, H.E., Paradise, J.L., Bluestone, CD., Blatter, M.M., Reisinger, K.S., Wald, E.R. and Sepance, J.S. (1991) Amoxicillin or myringotomy or both for acute otitis media: results of a randomized clinical trial. Pediatrics 87, 466-474. [18] Kayser, F.H., Morenzoni, G. and Santanam, P. (1990) The second European collaborative study on the frequency of antimicrobial resistance in Haemophilus influen::.ae. Eur. J. Clin. Microbiol. Infect. Dis. 9. 810-817. [19] Koomhof, H.J., Was as, A. and Klugman, K. (1992) Antimicrobial resistance in Streptococcus pneumoniae: A South African perspective. Clin. Infect. Dis. 15, 84-94. [20] Laurin, L., Prellner. K. and Kamme. C (1985) Phenoxymethylpenicillin and therapeutic failure in acute otitis media. Scand J. Infect. Dis. 17, 367-370. [21] Marchant. CD., Shurin, P.A., Johnson, CE., Murdell-Panek. D., Feinstein, J.C. Fulton. D .. Flexon. P., Carlin. S.A. and van Hare, G.F. (1986) A randomized controlled trial of amoxicillin plus c1avulanate compared with cefaclor for treatment of acute otitis media. J. Pediatr. 109. 891-896. [22] Melhus. A., Hermansson. A. and Pre liner. K. (1994) Nontypeable and encapsulated Haemuphilus injfuen::.ae yield different clinical courses of experimental otitis media. Acta Otolaryngol. (Stockh.) 114. 289-294. [231 Mygind, N., Meistrup-Larsen, N., Thomsen. J.. Thomsen, V.F., Josefsson, K. and Sorensen, H. ( 1981) Penicillin in acute otitis media: a double-blind placebo-controlled trial. Clin. Otolaryngol. 6. 5-13. [24] Molstad, S., Eliasson. I.. Hoveiius. B.. Kamme. C and Schalen, C (1988) Betalactamase production in the upper respiratory tract flora in relation to antibiotic consumption. Scand. J. Infect. Dis. 20, 329-334. [25] Nadal, D., Herrmann, P., Baumann, A. and Fanconi, A. (1990) Acute mastoiditis: clinical. microbiological, and therapeutic aspects. Eur. 1. Pediatr. 149, 560-564. [26] Ogle, 1. and Lauer, B. (1986) Acute mastoiditis. Diagnosis and complications. Am. 1. Dis. Child. 140,1178-1182. [27] Paiva, T. and Pulkkinen, K. (1959) Mastoiditis. 1. Laryngol. Otol. 73, 573-588. [28] Paiva, T., Virtanen, H. and Miikinen, 1. (1985) Acute and latent mastoiditis in children. 1. Laryngol. Otol. 99, 127-136. [29] Perrin, J.M., Charney, E .. MacWhinney, 1.B., Jr.. McInerny. T.K., Miller, R.L. and Nazarian. L.F. (1974) Sulfisoxazole as chemoprophylaxis for recurrent otitis media. A double-blind crossover study in pediatric practice. N. Eng\. J. Med. 291, 664-667. [30] Powell, M., McVey. D .. Kassim, M.H., Chen, H.Y. and Williams, 1.D. (1991) Antimicrobial susceptibility of Streptococcus pneumoniae, Haemophilus influen::.ae and Moraxella (Branham ella) catarrhalis isolated in the UK from sputa. J. Antimicrob. Chemother. 28,249-259. [31] Prellner, K. and Rydell, R. (1986) Acute mastoiditis. Influence of antibiotic treatment on the bacterial spectrum. Acta Otolaryngo\' (Stockh.) 102, 52 - 56.
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[32] Prellner, K., Fogle-Hansson, M., Jorgensen, F .. Kalm, O. and Kamme, C. (1994) Prevention of recurrent acute otitis media in otitis-prone children by intermittent prophylaxis with penicillin. Acta Otolaryngol. (Stockh.) 114, 182-187. [33] Principi, N., Marchisio, P .. Massironi, E., Grasso, R.M. and Filiberti, G. (1989) Prophylaxis of recurrent acute otitis media and middle-ear effusion. Comparison of amoxicillin with sulfamethoxazole and trimethoprim. Am. J. Dis. Child. 143. 1414-1418. [34] Rosen. A .• Ophir. D. and Marshak. G. (1986) Acute mastoiditis: a review of 69 cases. Ann. Otol. Rhinol. Laryngol. 95. 222-224. [35] Shurin. P.A. and van Hare, G.F. (1986) Therapy of acute otitis media caused by Branhamella catarrhalis. Preliminary report. Drugs 31 (Suppl. 3). 122-124. [36] Teele, D.W., Klein. J.O. and Rosner, B. (1989) Epidemiology of otitis media during the first seven years of life in children in greater Boston: a prospective, cohort study. J. Infect. Dis. 160, 83-94. [37] Williams, J.D., Powell. M., Fah, Y.S., Seymor, A. and Yuan, M. (1992) In vitro susceptibility of Haemophilus injiuenzae to cefaclor, cefixime, cefatemet and loracarbef. Eur. J. Clin. Microbiol. Infect. Dis. II, 748-751. [38] Zoller, H. (1972) Acute mastoiditis and its complications. South. M.J. 65, 477-553.
PediJ!ric
ELSE VIER
International Journal of Pediatric Otorhinolaryngology 32 (Suppl.) (1995) S145-S156
uto Rhino Laryngology
Symposium
Microbiology of acute otitis media and therapeutic consequences Karin Prellner*a (Chairman), Gunnar Kahlmeter b , Paola Marchisioc , Paul B. van Cauwenberged "Dept of Otorhinolaryngology, University Ho;,piWI, S-221 85 Lund, S.\'eden hDepartment of Clinical Microbiology, Central Hospital, ViixjO, Sweden 'Pediatric Dept, University of Milan, Milan, Italy "Dept of Otorhinolaryngology, University of Ghent, Ghent, Belgium
1. Introduction 'In 1992, 13,300 hospital patients died of infections that resisted every drug doctors tried' according to Newsweek (28 March 1994). Although this sentence did not allude to infections emerging from the upper respiratory tract, we are now facing a huge problem concerning increasing resistance to antimicrobial drugs among bacteria associated with acute purulent otitis media (AOM). Fig. I illustrates how the problem is escalating. It is obvious that new strategies for the use of antimicrobials are necessary. Before dealing with this question we will give background data and try to answer the central questions (I - IV) addressed in this symposium. 2. Question I: What is the clinical significance of various bacteria?
2.1. Therapeutic failures It is well known that the symptoms of AOM sometimes persist or recur during antibiotic therapy. However, the extent of such failure is still incompletely known, as is the cause of therapeutic failure, which has - apart from non-compliance been supposed to be due mainly to infection with microorganisms resistant to the drug used. In this respect interest has until recently focused on f3-lactamase-producing Haemophilus influen::ae and Moraxella catarrhalis.
* Corresponding author.
o165-5876/95/$09.5U
(1995 Elsevier Science Ireland Ltd. All rights reserved SSDI 0 165-5876( 94)0 1152-2
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Use 0/ antibiotics
TIIerfIPeutl.c shift towards broad spectrum (IJId/or
new antibiotics
/ncrusing Incidence 0/IlIIIimJcrobitzJ resislllnce to cllnictdly slgnl./lctllll levels
Fig. I. Escalating problems with use of antibiotics.
In a study of 75 children with therapeutic failures as judged by general practitioners (GP) and referred to an ENT-specialist for careful examination with otomicroscope and sampling of bacterial specimens, only II (15'1.,) fulfilled the criteria for a diagnosis of therapeutic failure, while 85% did not [20]. In 4/11 children no pathogens could be isolated and in the other 7 patients fJ -Iactamasenegative H. influen::ae were found in the middle ear effusion (MEE). Only one child showed growth of a fJ -Iactamase-producing M. catarrhalis, which was found in the nasopharynx (NPH) concomitantly with pure culture of non-fJ-lactamase-producing H. influen::ae in the MEE. In another study [12], 113 children were closely followed for three years from birth. Three hundred episodes of AOM occurred and 22 were instances of failure to respond to the primary antibiotic therapy. The risk of failure did not differ between the various drugs used but was significantly greater (fourfold) during the first year of life than during the following years. MEE/NPH specimens were collected before treatment in 17 of the 22 (77.7%) failures. Only 3 strains were in vitro found to be resistant to the drug used and were fJ-Iactamase-producing. It might be speculated· that one more such strain would have been identified if pretreatment cultures had been taken in all 22 instances. Thus, among 300 AOM episodes fJ-Iactamase-producing strains could have been responsible for the failure in 1.3 per cent (4/300). A similar percentage is obtained by calculation: about 20% of AOM is caused by H. influen::ae and 5%- 10% by M. catarrhalis, of which about 7% and 90%, respectively, produce fJ-Iactamase. Thus, '" 8% of all AOM episodes are due to fJ-Iactamase-producing bacteria. Since healing without treatment occurs in about 75% of AOM, fJ-Iactamase-producing
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bacteria might be suspected to contribute to unfavourable development in approximately 2'X, of AOM episodes. To conclude: the number of cases with therapeutic failure is highly overestimated unless the tympanic membrane is carefully examined, preferably by otomicroscopy. Being less than 1 year old constitutes a major risk factor for failure. In vitro testing of drug resistance in young children seems to have low predictive value. Although j3-lactamase-producing bacteria may cause failure during therapy of AOM [4,12,21,35], the results indicate that such bacteria might not be of major clinical importance. 2.2. Complications in A 0 M Acute mastoiditis is most common in children below 2 years. The incidence requiring operation declined steeply after the introduction of antimicrobial agents such as sulphonamide and penicillin G. A further decrease in the incidence has occurred during the past three decades [28]. However, the proportion of more serious complications (meningitis, epidural abscess, sepsis, death) to acute mastoiditis does not seem to have decreased [10,38]. What is then our knowledge concerning bacteria in conjunction with acute mastoiditis? In 29 children, median age 13 months, with clinical signs of acute mastoiditis and in whom mastoid ectomy and myringotomy were undertaken between 1970 and 1989, bacteriological examinations were performed [31]. With the exception that no strain of M. catarrhalis was found, different results were obtained when analysing the children with (n = IS) and without (n = 14) antibiotic treatment prior to admission (Table I). In the patients without antibiotic pre-treatment, pneumococci or j3-hemolytic streptococci were isolated in 10/14 cases. No isolates of H. injluenzae were found (Table I). As illustrated in Table I, pneumococci and j3 -hemolytic streptococci are the major pathogens in acute mastoiditis [9,10,13,14,25,27,28,34]. H. injluenzae is an infrequent finding and no strain has been reported to produce j3-lactamase. In the
Table 1 Reported bacteriological findings in acute mastoiditis (,1.,) Reference
Period
Beta-hemolytic streptococci
Pneumococci
[27] [10] [28] [ 13]
1954-1958 1955-1980 1974-1982 1972-1982
31 16 8 44
13 29 42 33
4 2 8 0
[31], [32]
1970-1984 Without abo With abo
9 18 0
36 54 18
14 0 28
H. influen:ae
No pathogens 27 20 25 Only those with positive culture were included 23 0 45
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few studies where capsulation was looked for, the H. influenzae strains were found to be encapsulated (type b) [10,25,26,28]. M. catarrhalis was not found in any of the studies. In the literature only one case report was found - in non-immunocompromised host - where an invasive infection in connection with otitis media might have been caused by a Moraxella strain. To conclude: pneumococci and f3-hemolytic streptococci are by far the most important bacteria concerning risk for complications. Based on present knowledge - including experimental otitis media studies [22] - it could be doubted whether unencapsulated H. injluenzae or M. catarrhalis have to be feared in the context of serious complications to AOM. 3. Questions II, III. Antimicrobial resistance in bacteria causing acute otitis media Streptococcus pneumoniae, Haemophilus injluenzae and Moraxella catarrhalis cause more than 90% of all AOM episodes. In each of these species, major resistance development to clinically useful antimicrobial agents has occurred over the past 20 years. In some parts of the world antimicrobial resistance development has reached proportions where the choice of antimicrobial therapy is severely restricted and where public media have started to take notice (Newsweek. 28 March 1994). Streptococcus pneumoniae that are inhibited by benzylpenicillin concentrations of ~ 0.1 mg/I are internationally considered susceptible and clinically available with standard f3 -Iactam dosages. Strains requiring ;;:: 2.0 mg/I are considered resistant and not therapeutically available with f3-lactam drugs. Significant penicillin resistance in S. pneumoniae was reported from South Africa in 1977 by Appelbaum and co-workers [1]. and shortly after multiply drug resistant S. pneumoniae were isolated by Jacobs et al. [16]. In South Africa the incidence of penicillin resistance has increased from approximately 5% in 1980 to 15% in 1990 [19]. The mechanism for penicillin resistance, the alteration of an essential penicillin binding protein (PBP2). affects the activity of all f3-lactam drugs including cephalosporins. imipenem and meropenem. Penicillin-resistant S. pneumoniae exhibit minimum inhibitory concentrations (MICs) for cephalosporins, imipenem and meropenem which are clearly higher than those seen in strains susceptible to penicillin (Table 2. compiled from [15]). In severe or complicated infections it is prudent to consider penicillin-resistant S. pneumoniae resistant to all f3-lactam drugs. In S. pneumoniae resistance mechanisms to virtually all clinically useful antimicrobial agents, including new macrolides and quinolones. have now been described. Erythromycin resistance automatically confers resistance to roxithromycin, clarithromycin and azithromycin and resistance to one quinolone would automatically render other quinolones useless. The international magnitude of the problem is shown in Table 3. Local outbreaks with one or more strains exhibiting multiple resistance have occurred in several countries such as South Africa, USA, Spain and Iceland. Hitherto the strains have always been susceptible to vancomycin if nothing else.
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Table 2 S. pneumoniae and betalactam cross resistance (compiled from [15]) Strains classified according to benzylpenicillin MIC (mg/I) Betalactam drug
Susceptible
Intermediate
Resistant
Benzylpenicillin (PeG) Ampicillin Cefaclor Cefotaxime Cefuroxime Ceftazidime Ceftizoxime Cefexime Cefoperazone Cefpirome Imipenem Meropenem
<0.03 <0.03 0.5 <0.06 0.06 0.25 0.5 0.5 0.12 0.01 <0.03 <0.03
0.5-1 0.5-1 32 0.25-0.5 2 32 16 16 1-2 0.5 0.25-1 0.25-1
4-16 8 64 1-4 16 64 32 32 2-8 I 0.5-2 0.5-2
Table 3 Antimicrobial resistance in Streptococcus pneumoniae in various countries in the period 1988- 1992 Country
South Africa Spain France Hungary Iceland USA Sweden UK
Penicillin
Erythromycin
Tetracycline
15'X, 13%
9(1..
I21Y;.
26(!~,
20 11.)
47% 15%
44(~;;1
59%
<1%
6(Yc) 2(1.)
2(X)
3('/0
T'/o
g(Yt)
1(;;.
Trimethoprim sulphamethoxazole
38%
In Haemophilus injluenzae, resistance to penicillins, tetracyclines and chloramphenicol was described in the 1970s. Resistance to trimethoprim - sulphamethoxazole and more recently to quinolones is emerging. There are two completely different mechanisms of penicillin resistance. One is due to the formation of fJ-lactamase mediated by at least two different plasmids of which the TEM-I-plasmid is the most common. The other mechanism is chromosomally mediated and involves alteration of penicillin binding proteins. The activities of various fJ-lactam drugs to strains with penicillin resistance mechanisms are summarized in Table 4. The clinical significance of fi-lactamase production is undisputed whereas the relevance of penicillin resistance in fJ-lactamase-non-producing H. injiuen::ae is unclear [37]. To be conservative such strains should be assumed to be clinically resistant to other fJ-lactam drugs [2].
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Table 4 Antimicrobial activity of betalactam drugs to Haemophilus injluenzae with betalactamase production or chromosomally mediated betalactam resistance Antimicrobial agent
Betalactamase resistance
Chromosomal resistance
Benzylpenicillin (PeG) Phenoxymethylpenicillin (PcV) Ampicillin Ampicillin + c1avulanic acid Cephalosporins Imipenem, Meropenem
No activity No activity No activity Active Active Active
No activity No activity No activity No activity Variable activity Variable activity
H.il'lfluenzae and betalactamase in Europe 1988/89
(compiled from re'entnce18)
!ta!Y Austria Germany (W) United KingdOm Netherlands Belgium Switzerland
!;;;""-----~==l
:
i:: ~b
" k:: I
~==;;;;~~~~__~~~~ o 20 40 60
France Spain II!!
Betalactamase (%)
Fig. 2. H. injluenzae and betalactamase in Europe 1988 - 1989 (compiled from [18]). Table 5 Antimicrobial resistance in Haemophilus injluenzae in various locations in the period 1988 - 1992 Location
Betalactamase resistance
Chromosomal Chloramphenicol penicilIinresistance
Tetracycline
Trimethoprimsulphamethoxazole
USA (1986) Europe (1989) UK Sweden
20'1., 9%
2% 2%
1%
2%
3'0,
5'Yo
0.3u!t, 7%
10%
1%
1%
5% 1%
8%
9(X)
5(X)
Fig. 2 shows the frequency of p-Iactamase-producing H. injluenzae type band non-type b in some European countries (data from [18]). It is evident that p-lactamase production is neither more nor less common in type b strains. Antimicrobial resistance development in H. injluenzae is summarized in Table 5. It is doubtful whether true erythromycin resistance (presence of resistance mechanism) occurs in H. injluenzae. The huge variation in erythromycin resistance
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Table 6 Erythromycin MIC-breakpoints in various countries Country
Regulatory body
Susceptible (mgjl)
Resistant (mgjl)
USA UK France Germany Netherlands Sweden
NCCLS BSAC SFM DIN WRG SRGA
::0;2 ::0; 0.5 ::0;1 ::0;1 ::0;1 ::0; 0.5
:2:8 >0.5 >4 :2:8 :2:4 :2:8
frequencies between countries is above all an expreSSIOn of lack of consensus concerning the MIC-breakpoints (Table 6). In Moraxella catarrhalis the frequency of {3-lactamase-producing strains increased rapidly during the 1980s. {3-lactamase-production is mediated by either of two plasmids, the BRO-l or BRO-2 plasmids, of which the BRO-l is much more common. In Europe ~ 80% of M. catarrhalis produce {3-lactamase [24.30]. The organism is intrinsically resistant to trimethoprim, clindamycin and vancomycin but is often susceptible to sulphamethoxazole, tetracycline and quinolones (resistance < 5'Y.,). In contrast, among the {3-hemolytic group A streptococci, which are the causative agent ill 5%-IO'Yo of AOM, no penicillin-resistant strains have been reported. To conclude: it is necessary to reach a consensus on MIC-breakpoints to facilitate international understanding. The strategies for antimicrobial therapy in AOM must be adapted to local frequencies of antimicrobial resistance. 4. Question IV. Must antibiotics be used at all in treatment and prevention?
4.1. Treatment or no treatment of acute episodes of A 0 M? Since the 1950s the standard treatment of AOM has included antibiotics and analgesics (and sometimes myringotomy). One rationale for this was to decrease the rate of complications. This standard treatment has, however, been questioned during the 1980s [6,7,23]. In the study by Mygind et al. [23] where penicillin V was compared to placebo, 149 children between 1 and 10 years were investigated. Patients were excluded during follow-up 'if complication threatened or another disease required antibiotic treatment'. The results showed satisfactory results in 86% of those treated with penicillin as compared with 69% of those given placebo. The study was rather small and no reliable conclusions vis-a-vis the occurrence of serious complications could be drawn. The authors concluded that an attitude of 'masterly inactivity' regarding antibiotics is justified provided there are reasonable provisions for continued observation of the child. The few studies by other authors in which the effect of antibiotic treatment was compared with that of placebo point in the same direction - some superior effect of antibiotics but high cure rates also on placebo.
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In 1981 van Buchem et al. [6] published the outcome of various 'treatments' in AOM. The objective of the study was to compare the outcome of four different treatment methods: (I) only symptomatic treatment, (2) antibiotics + symptomatic treatment, (3) myringotomy + symptomatic treatment and (4) myringotomy + antibiotics + symptomatic treatment. The study subjects were 171 children, 2 years and older, with 239 affected ears. The diagnosis of AOM was made by a GP and confirmed by an ENT specialist. In only 2 cases was there a disagreement on diagnosis between the ENT specialist and the GP, which is less than I %! The parameters studied were: degree of earache, ear discharge, otoscopic findings, temperature, use of analgesics, relapses, 'irregular course' and complications. The results were rather surprising and gave rise to a lot of discussion in scientific meetings and journals. Indeed, the authors did not find a statistically significant difference between the four treatment groups, except that there were more discharging ears in the myringotomy groups and that the temperature after 24 h was higher in the myringotomy alone group. In the groups treated with antibiotics, the ears discharged for slightly longer and the tympanic membranes took a little longer to heal, but these differences were not significant. There were only four 'irregular courses' and there was no report of mastoiditis or other complications. The authors concluded that symptomatic treatment with vasoconstricting nose drops and analgesics seems to be a reasonable initial approach to AOM in children and that myringotomy and antibiotics can be reserved for cases in which the course of otitis is irregular or if there are complications. Some critical observations on this study included the fact that only children of 2 years and older entered the study, the doubts about accurate diagnosis (AOM or SOM?) and the remark that the series were not large enough to estimate the complication rate. Looking at the diagnostic criteria used and the symptoms of the children included in these studies, they would probably not have been treated by antibiotics in a clinical setting anyway. In another study by van Buchem et al. [7], 4860 children, 2 years and older, with AOM were treated with symptomatic treatment (by GP). They were referred to an ENT specialist in case of an unsatisfactory course. There were only 126 cases (2.7°;;,) with a severe course (1 with mastoiditis); group A streptococci were identified in 30 of them, and H. influen;;;ae only once. Seventy children (1.4'%) had ear discharge lasting longer than 14 days. Since these studies it has become more and more popular, especially among Dutch GPs, not to treat AOM with antibiotics. Today less than 40% of them still give antibiotics in case of AOM in a child older than 2 years. In other parts of the world nearly 100'Y<, of GPs, pediatricians and otolaryngologists give antibiotics. In a more recent study, Kaleida et al. [17] compared the effect of amoxycillin with that of placebo in children with non-severe acute otitis. In the group under the age of 2 years there were no significant differences with regard to the initial treatment failure, the presence of effusion at 6 weeks and the recurrence of AOM; there was, however, a significant difference (P < 0.001) with regard to the presence of an effusion at 2 weeks (52% in the amoxycillin group vs. 68% in the placebo group). For the children older than 2 years, there were no significant differences
K. Prellner el al.j In!. J. Pedialr. Otorhinolaryngol. 32 (Suppl.) (1995) S145-S156
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with regard to the presence of effusion at 6 weeks and the recurrence of AOM, but there were significant differences with regard to the initial treatment failure (0.5'% in the amoxycillin group vs. 5.5% in the placebo group; P = 0.005) and with regard to the presence of effusion at 2 weeks (41 'Yo in the amoxycillin group vs. 56% in the placebo group; P = 0.01). To conclude: there is a need for a careful interpretation of the results without too much extrapolation and always bearing in mind that the physician has to treat individual cases and not trial populations. 4.2. Prevention of recurrent acute otitis media More than 40% of children experience three or more episodes of AOM in the first 3 years of life [36]. Because short- and long-term consequences may have great medical and social impact, prevention is strongly suggested at least in children with recurrent episodes in a short period of time. Among the various approaches - chemoprophylaxis, immunoprophylaxis, surgery and, more recently, control of environmental risk factors - antibiotic prophylaxis is today considered the best medical option. Different schemes of prophylaxis have been used: from sulfonamides given twice daily for 3 months only during the winter season [29] to amoxicillin given once daily for 6 months, irrespective of the season [33]. A recent metanalysis of randomized clinical trials confirmed that all the drugs and all the schemes used for prophylaxis are effective in preventing recurrences [5]. Despite this, many questions regarding the time of beginning, the mode of administration and the duration of prophylaxis remain unsolved. Moreover, still debated are the problem of compliance with a long-term treatment and that of the possible emergence of resistant strains. Prophylaxis' is traditionally given to children who have had three documented episodes of AOM in 6 months or four episodes in 12 months. Recently it was demonstrated that amoxicillin prophylaxis can reduce the risk of further episodes of AOM in children who had their first AOM before the first birthday. This would suggest that in younger children prophylaxis should be initiated after the second episode 'of AOM. Intermittent prophylaxis (given only when the child develops respiratory symptoms) could theoretically be more suitable for children. However, its efficacy has not always been demonstrated to be equivalent to that reported for .continuous prophylaxis [3,32]. Compliance with prophylaxis can be quite different according to the scheme' of antibiotic administration and the socioeconomic status of the child's family [II]. To improve compliance, the use of long-acting antibiotics may be a possibility. Recently azithromycin, a new macrolide with pharmacokinetic characteristics that permit, despite a once a week administration, continuous therapeutic levels in the MEE, has been demonstrated to be as effective as amoxicillin given daily in preventing AOM (Principi et aI., in progress). Antibiotics have been given for periods ranging from 3 months to 2 years and the current recommendation is to give prophylaxis for approximately 6 months, but there are no conclusive data concerning the optimal duration.
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Fortunately, the emergence of resistant bacterial strains possibly causing AOM during antibiotic prophylaxis has not been proved [8,36]. However, conclusive studies regarding possible modifications of bacterial flora present in various body sites are still lacking. To conclude: antibiotic prophylaxis remain the best medical approach to recurrent AOM. However, a lot of problems remain unsolved and further studies are needed to optimize drug administration. 5. Needs and strategies
Although the problems addressed in this symposium focused on AOM, the needs and strategies for the near future must, due to the present situation with fast emergence of multiresistant bacterial strains, also include general recommendations. (1) We need new antimicrobials with truly new modes of action (a new macrolide or cephalosporin does not solve the problem). (2) The use of antimicrobials as growth or yield promo tors in fish and farming industries must now be seriously questioned. (3) Epidemiological national surveillance must be intensified. (4) To facilitate international understanding, a consensus on MIC-breakpoints must be reached. (5) It is necessary to adopt even more stringent criteria for antimicrobial therapy/ prophylaxis. (6) Strategies for antimicrobial therapy must be adapted to local frequencies of antimicrobial resistance and must include a predetermined therapeutic variability to avoid selection of resistant clones. References [I] Appelbaum, P.c.. Bhamjee, A., Scragg, J.N., Hallett, A.F., Bowen, A.J. and Cooper, R.C. (1977) Streptococcus pneumoniae resistant to penicillin and chloramphenicol. Lancet 2, 995-997. [2] Barry, A.L.. Fuchs. P.c. and Pfaller, M.A. (1993) Susceptibilities of p-Iactamase-producing and non producing strains of Haemophilus irif/uenzae to ceftibuten, cefaclor, cefuroxime, cefixime, cefotaxime, and amoxicillin-clavulanic acid. Antimicrob. Agents Chemother. 37, 14-18. [3] Berman, S., Nuss, R., Roark, R., Huber-Navin, C., Grose, K. and Herrera, M. (1992) Effectiveness of continuous vs. intermittent amoxicillin to prevent episodes of otitis media. Pediatr. Infect. Dis. J. 11, 63-67. [4] Bluestone, C.D. (1986) Otitis media and sinusitis in children. Role of Branhamella catarrhalis. Drugs 31 (Suppl. 3), 132-141. [5] Bonati, M., Marchetti, F., Pistotti, V. et al. (1992) Meta-analysis of antimicrobial prophylaxis for recurrent acute otitis media. Clin. Trials and Meta-analysis 28, 39-50. [6] Buchem, F.L. van, Dunk, J.M. and van't Hof, M.A. (1981) Therapy of acute otitis media: myringotomy, antibiotics, or neither? A double-blind study in children. Lancet, 24, Oct., 883-887. [7] Buchem, F.L. van, Peeters, M.F. and van't Hof, M.A. (1985) Acute otitis media: a new treatment strategy. Br. Med. J. 290, 1033-1037. [8] Cassel brant, M.L., Kaleida, P.H., Rockette, H.E., Paradise, J.L., Bluestone, C.D., Kurs-Lasky, M. et al. (1992) Efficacy of antimicrobial prophylaxis and of tympanostomy tube insertion for prevention of recurrent acute otitis media: results of a randomized clinical trial. Pediatr. Infect. Dis. J. 111, 278-286.
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