Drugs 34 (Suppl. I): 139-143 (1987) 0012-6667/87/0100-0139/$2.50/0 ©ADlS Press Limited All rights reserved.
Chemotherapy of Otitis Media with Ofloxacin T. Lenarz ENT Department of the University of Heidelberg, Heidelberg
Summary
This study evaluated the therapeutic role of oj/oxacin in different forms of otitis media. After identifying the infecting bacteria in 250 patients with acute otitis media. or chronic otitis media. the clinical efficacy of orally administered ojloxacin 200mg twice daily was assessed in 45 patients from each of these groups. The clinical results were comparable with those obtained after conventional local and oral antibiotic therapy. Microbiological examination ofthe ear secretions revealed Staphylococcus aureus, Streptococcus pyogenes, Streptococcus pneumoniae and Haemophilus influenzae to be the main pathogens in acute otitis media. whereas in chronic otitis media P. aeruginosa and Proteus sp. were detected in most ofthe cases. Ojloxacin concentrations in secretions and mucosa specimens ofthe middle ear exceeded serum concentrations by more than Z-fold. On the basis of these preliminary results. ojloxacin appears to be an effective orally administered agent, without ototoxicity. which is effective against S. aureus and P. aeruginosa, 2 important pathogens in middle ear infections. Ofloxacin should be considered as an alternative for the therapy of otitis media. especially the chronic forms .
In nearly all cases of acute , as well as chronic, otitis media, infecting bacteria can be identified and quantified by means of microbiological examination. For proper antibacterial chemotherapy and the clinical evaluation of new antibiotics, acute and chronic forms of otitis media have to be distinguished because the bacterial spectra and clinical features show important differences. In addition, the fluid and mucosal concentrations of the antibiotic drug should be much higher than the minimum inhibitory concentrations (MIC), which must be low for the relevant bacteria, and there should be no potential risk of ototoxicity. However, proper clinical evaluation of a new agent demands a comparison of the clinical results with those of
routine management with oral penicillin for acute otitis and combined local!oral antibiotic therapy, as well as middle ear surgery, for the chronic forms. Considering these points, the following study was performed to evaluate the clinical efficacy and safety of ofloxacin in middle ear infections. The data accompany and expand on results previously reported (Lenarz 1986a,b).
1. Materials and Methods 1.1 Characteristics of Otitis Media Acute otitis media is characterised by an acute onset of pain, hearing loss and sometimes secretion following perforation of the tympanic membrane
Chemotherapy of Otitis Media
140
in 1 or both ears. The disease is self limiting, normally lasting for 7 to 10 days. Its duration is usually assessed as the time required for normalisation of the ear drum and hearing. Chronic forms of otitis media are characterised by recurrent fluid secretion and permanent conductive hearing loss due to perforation of the tympanic membrane and damage to the ossicular chain. Diagnosis was made by otoscopic examination and microscopy. Fluid specimens were taken from the outer ear canal and mucosal specimens were taken through perforations of the ear drum. 1.2 Microbiology In 65 cases of acute otitis media, 88 of otitis media chronica mesotympanalis and 97 of otitis media chronica epitympanalis, the infecting organisms in middle ear secretions were ascertained by use of culture methods. Sensitivites to ofloxacin were determined by the agar diffusion test. 1.3 Treatment Schedule 45 patients from each group with acute otitis media, otitis media chronica mesotympanalis and otitis media chronica epitympanalis were treated with ofloxacin 200mg twice daily for 7 to 20 days. After 2 days of treatment, a sample of secretion
or a specimen of middle ear mucosa was taken simultaneously with a sample of venous blood for determination of drug levels. The results were compared with those of conventional local and oral antibiotic treatment; namely, ear drops containing chloramphenicol, tetracyclines or aminoglycosides and oral penicillin. 1.4 High Performance Liquid Chromatography Analysis The ofloxacin concentrations in middle ear mucosa, middle ear secretion and plasma were determined by high performance liquid chromatography (HPLC) [Verho et a1.1985] in 12 patients (4 from each group) 2 hours after the last oral dose of 200mg.
2. Results 2.1 Bacteriology The bacterial pathogens identified in the several forms of otitis media and the proportions susceptible to ofloxacin are shown in table I. Staphylococcus aureus, Streptococcus pyogenes, Streptococcus pneumoniae and Haemophilus influenzae were the predominant bacteria in acute otitis media, whereas Pseudomonas aeruginosa and Proteus sp. were most frequently identified in otitis media chronica
Table I. Bacterial pathogens isolated from 250 patients with otitis media
Staphylococcus aureus Streptococcus pyogenes Haemophilus influenzae Proteus sp. Pseudomonas aeruginosa Escherichia coli Streptococcus pneumoniae
= 88)
AO (n = 65)
OCM (n
no./%/MICgo (mg/L)
no./%/MIC90 (mg/L)
19/95/0 .21 33/85/0 .91 35/97/0 .45 5/80 9/85/0.91
OCE (n = 97) no./%/MIC90 (mg/L)
32/88/0 .33 18/91/1.23
25/90/0 .26 9/100/1.17
47/93 37/82/1 .38 15/100/0.16 9/44/2 .31
58/90
21100
28/63
95/91/1.2 9/88/0.17
Abbreviations: no. = number of patients ; % = percentage of bacterial strains which are susceptible to ofloxac in; AO = acute otitis
media; OCM- '" otitis media chronica mesotympanalis ; OCE
= otitis
media chronica epitympanalis .
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141
Table II. Clin ical course of acute otitis media during treatment with ofloxacin or pen icillin Ofloxacin
Oral pen icillin
(n
(n
= 45)
=
38)
Duration of pain (days)
3.6 ± 1.7
3.7 ± 1.8 (ns)
Durat ion of secret ion (days)
4.6 ± 1.9
5.7 ± 2.9 (ns)
Time for ear drum to normal ise (days)
11.7 ± 6.5
14.5 ± 8.1 (ns)
Successful treatment (% of patients)
86
79 (ns)
ns = non-signif icant difference between treatments, t-test.
Table III. Clin ical course of chron ic otit is media during ofloxacin or local treatment Ofloxacin (n
=
40)
Local treatment (n
= 36)
4.5 ± 2.7 (ns)
3.4 ± 2.5 6.1 ± 4.3
8.2 ± 5.4 (ns)
Time for ear drum to normal ise (days)
16.6 ± 7.7
15.7 ± 7.4 (ns)
Successful treatment (% of patients)
91
83 (ns)
Duration of pain (days) Durat ion of secret ion (days)
ns
= non-sign ificant difference between
treatments, t-test,
mesotympanalis and otitis media chronica epitympanalis. The high percentages of strains sensitive to ofloxacin demonstrate the broad antibacterial spectrum of this agent. Ofloxacin was less effective against S. pneumoniae, which plays a role only in acute otitis media. About 10 to 20070 of Pseudomonas strains were resistant to ofloxacin. 2.2 Clinical Effects The clinical course for both acute otitis media and chronica mesotympanalis during treatment with ofloxacin was comparable to conventional treatment (tables II and III). Although the duration of disease periods was shorter with ofloxacin, the differences were not statistically significant. Adverse reactions were rare and disappeared within 24 hours after termination of ofloxacin treatment. Two patients experienced gastric pain and one a skin rash .
2.3 Tissue and Fluid Ofloxacin Concentrations The ofloxacin concentrations in middle ear mucosa and secretions were more than twice those in plasma in the 12 patients studied (table IV).
3. Discussion Microbiological analysis revealed a broad spectrum of bacteria associated with otitis media. The therapeutic potential of ofloxacin in otitis media was indicated by sensitivity data and high middle ear tissue and secretion concentrations of ofloxacin . Although about 30 to 50070 of strains of S. pneumoniae showed in vitro resistance to ofloxacin, this organism is pathogenic only in the acute form of otitis media. A similar pattern of results was obtained in patients with chron ic bronchitis (Davies et al. 1986). Reported MIC go values against S. pneumoniae (Seibert et al. 1986) are higher than those against other bacteria represented in otitis media, being close to the concentrations of ofloxacin measured in plasma. Therefore, the risk of resistance developing during therap y against this pathogen is increased. Since routine oral penicillin therap y is equally effective, ofloxacin cannot be recommended as the drug of first choice for routine therapy of otitis media. The main advantage of ofloxacin over conventional therapy is that it possesses good antibacterial activity against P. aeruginosa, an important pathogen in chronic otitis media. Previously, eradication of this organism required either local treatment with ear drops containing
Table IV. Ofloxacin concentrations after 2 days ' adm inistration of 200mg twice daily Ofloxacin
Ratio to
concen trat ion
plasma
(mg/L ; n
concentration
= 12)
Plasma
2.3 ± 1.9
Ear secretion
5.1 ± 2.5
2.2
Mucosa
6.2 ± 2.5
2.7
142
Chemotherapy of Otitis Media
chloramphenicol or aminoglycosides (with the potential risk of ototoxicity), or hospitalised systemic antibacterial treatment (Breuninger 1983; Federspil 1982). In contrast to acute otitis media, otitis media chronica mesotympanalis does not feature bacteria as the predominant aetiological factor. Rather, they are responsible for the acute suppurative exacerbations of the underlying chronic immunodeficient inflammation of the middle ear mucosa, and it is these exacerbations that require antibacterial treatment. Administration of an antibiotic is also required peri- and post-operatively in otitis media chronica epitympanalis. About 10 to 20% of the strains of P. aeruginosa were found to be resistant in the susceptibility tests. Since there was no prior therapy with ofloxacin, a primary type of resistance can be considered. However, all patients were previously treated with other antibiotics such as aminoglycosides, chloramphenicolor tetracyclines, which could have induced cross-resistance (Smith 1984). The development of resistance during continuing therapy was not followed up . The in vitro test results could be confirmed by our clinical observations together with the measurements of drug levels. Oral therapy with ofloxacin was as effective as conventional therapy in both acute and chronic otitis media. These favourable results are further supported by the drug levels in the middle ear, which far exceeded the MICs of nearly all bacterial pathogens found in otitis media (Duben et al. 1986). Furthermore, the very low rate of adverse effects, especially the lack of ototoxicity, supports the use of ofloxacin as an agent of choice in chronic otitis media, especially when P. aeruginosa has been identified and the condition is unresponsive to other therapeutic regimens. Ear drops containing ofloxacin should also be tested for their efficacy and possible ototoxicity (Stille 1986).
Acknowledgement The microbiological tests were performed by the HygieneInstitut , Heidelberg University (Chairman: Prof. Dr Sonntag). The author is grateful for this collaboration .
References Breuninger H. Medikarnentose Therapie der Hals-NasenOhrenkrankheiten, Thieme Verlag, Stuttgart, 1983 Davies BI, Maesen FPV, Teengs JP, Baur C. Neue orale Chinolon-Verbindungen bei chronischer Bronchitis. Infection 14 (Suppl. I): 73-78, 1986 Diiben W, Student A, Jablonski M, Malottke R. Zur Gewebekonzentration und Wirksamke it von Ofloxacin bei chirurgischen Patienten . Infection 14 (Suppl. I): 70-72,1986 Federspil P . Ototoxizitat von Antibiotika unter besonderer Beriicksichtigung der Lokalbehandlung . In Ganz & Schatzle (Eds) HNO Praxis heute, Vol. 2, pp.2-33, Springer Verlag, Berlin, 1982 Lenarz T . Ofloxacin in der konservativen Therapie der akuten und chronischen Otitis media - Ein vorlaufiger klinischer Erfahrungsbericht. Infection 14 (Suppl. I): 87-88, 1986a Lenarz T. Ofloxacin in oral chemotherapy of acute and chronic otitis media. Infection 14 (Suppl. 4): 324-326, 1986b Seibert G, Isert 0, KIesel N, Limbert M, Schrinner E, et al. Die antibakterielle Aktivitat von Ofloxacin . Fortschritte in der Antimikrobiellen und Antineoplastischen Chemotherapie 5-5: 773-779, 1986 Smith JT . Mutational resistance to 4-quinolone antibacterial agents. European Journal of Clinical Microbiology 3: 347-350, 1984 Stille W. Antibakterielle Zemente, Plomben und Lacke. Miinchener MedizinischeWochenschrift 128(Suppl. 24): 7-8, 1986 Verho M, Malerczyk V. Dagrosa EE. Korn A. Dose linearity and other pharmacokinetics of ofloxacin: anew, broadspectrum antimicrobial agent. Pharmatherapeutica 4: 376-382, 1985 Author's address : Dr med. T. Lenarz, Univ. HNO-Klinik, Vosstrasse 5-7, 0-6900 Heidelberg (Federal Republic of Germany) .
Discussion Question: Is benzylpenicillin an adequate standard treatment, bearing in mind your reference to the presence of Pseudomonas and Haemophilus influenzae? Answer: Oral penicillin is effective in acute otitis media where streptococci or staphylococci are the usual pathogens. It is not effective in chronic forms that require local treatment with agents effective against Pseudomonas. Question: How does a locally administered quinolone compare with other locally applied drugs? Answer: Substances that are effective against Pseudomonas, particularly gentamicin and neomycin, tend to cause ototoxicity. This has not been a problem in our experience with oral ofloxacin. It should be noted that in otitis externa, the in-
Chemotherapy of Otitis Media
fection is localised under the skin and it is not treatable with ear drops. Question: In patients with chronic otitis media, what were the durations of the treatment and follow-up periods , and how often was surgery performed?
143
Answer: Surgery was performed in allicases, since antibacterial treatment alone will not cure the condition. Therapy usually lasted for I to 2 weeks and follow-up has continued for nearly I year.
