S. Vb:tanen, E . - A . L a h i k a i n e n

Ampicillin Concentrations in Middle Ear Effusions in Acute Otitis Media after Administration of Bacampicillin Summary: The penetration of ampicillin into middle ear effusions after oral administration of 800 mg bacampicillin to patients with acute otitis media was studied and compared with the serum levels. One hour after administration a mean (+_ SEM) concentration of 2.4 _+ 0.4 ~g/ml ampicillin was found in the effusions and the mean serum level was 7.7 _+ 0.8 ~ag/ml. After twelve hours a mean concentration of 0.6 ___ 0.2 t~g/ml was found in the middle ear effusions and 0.1 _ 0.03 lag/ml in the serum. The high concentration of ampicillin in middle ear effusions after twelve hours suggests that a twice daily dosage of bacampicillin should be given in acute otitis media. Zusammenfassung: Ampiciltin-Konzentrationen in Mittelohrsekreten bei akuter Otitis media nach Gabe yon Bacampicillin. Die Penetration von Ampicillin in das Mittelohrsekret nach oraler Gabe von 800 mg Bacampicillin unter vergleichender Beriicksichtigung der Serumspiegel wurde bei Patienten mit akuter Otitis media untersucht. Eine Stunde nach Verabreichung des Medikaments wurde in den Sekreten eine mittlere Konzentration von 2,4 --+ 0,4 pg/ml Ampicillin gefunden; der mittlere Serumspiegel betrug 7,7 + 0,8 ~tg/ml. Nach zw61f Stunden land sich eine mittlere Konzentration yon 0,6 + 0,2 ~tg/ml in den Mittelohrsekreten und von 0,1 + 0,03 lag/ml im Serum. Aus der hohen Konzentration yon Ampicillin in Mittelohrsekreten nach zw61f Stunden kann eine zweimal t~igliche Dosierung von Bacampicillin bei Otitis media abgeteitet werden.

mean weight was 59.U _+- 2.8 kg (range 20-80 kg ), and the mean age was 32.2 _+ 3.0 years (range 5-80 years). All patients had an acute onset with severe pain. The tympanic membrane was red and sometimes bulging. Patients with a previously established allergy to penicillin, patients treated with antibiotics during the last seven days, patients with infectious mononucleosis, and patients with both tympanic membranes which ruptured spontaneously before treatment were excluded from the trial, "Iqae patients were given 800 mg of bacampicillin orally, (two tablets of 400 mg). In twenty patients blood samples and samples of ear effusion were taken one hour after admirdstration of the first dose of bacampicillin; in fourteen patilents the samples were taken after twelve hours. In six patients samples were taken at different times 20-45 minutes after administration of the antibiotic in order to see how fast concentrations of ampicillin were achieved in the middle ear effusions and serum. Blood samples were taken by

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Bacampicillin is a n e w semisynthetic derivative, the hydrochloride of l'-ethoxy-carbonyl-oxyethyl-6-D(D-c~a m i n o p h e n y l a c e t a m i d o ) penicillinate (Figure 1). It was s y n t h e t i z e d by the A s t r a L/~kemedel L a b o r a t o r i e s , S t d e r -

Figure l: Structure of bacampicillin hydrochloride and of ampicillin.

t~ilje, Sweden. Following oral administration, bacampicillin is rapidly conv e r t e d into ampicillin and no u n c h a n g e d c o m p o u n d has b e e n d e t e c t e d in t h e b l o o d (1). Bacampicillin is a b s o r b e d m o r e rapidly and m o r e c o m p l e t e l y t h a n ampicillin and thus gives higher s e r u m levels (2). H i g h c o n c e n t r a t i o n s are also a t t a i n e d in urine, saliva, lacrimal and skin blister fluid (3). T h e p e a k s e r u m level is achieved a p p r o x i m a t e l y one h o u r after oral a d m i n i s t r a t i o n of bacampicillin (2, 3). A f t e r twelve h o u r s only traces of the drug are f o u n d in s e r u m (2). T h e p u r p o s e of this investigation was to study the c o n c e n trations and p e r s i s t a n c e of ampicillin in s e r u m and in m i d d l e ear effusions one and twelve h o u r s after a single oral dose of bacampicillin.

venepuncture. Samples of ear effusion were taken by aspiration of the punctured middle ear cavity by means of Lahikaiuen's needle and a plastic syringe (Figure 2). If the fluid was tinged with blood the sample was excluded. The aspirated fluid was expelled through the needle into a small disposable micro-centrifuge tube (Figure 2), and sent immediately to the National Public Health Laboratory in Turku. The samples were stored in a refrigerator and bacterial cultures and antibiotic assays were carried out the same day. Samples taken in the afternoon were stored in a refrigerator and analysed the next day. The drug concentrations were determined by a micro-technique (4), Penassay seed agar (Difco) and Sarcina lutea ATCC 9341 were used for all determinations. The standard series of ampicillin were obtained from Biodisk AB, Sweden,

Materials and Methods The material consisted of 40 ambulant patients with acute otitis media. There were 22 males and 18 females in the series. The

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Infection 7 (1979) Suppl. 5

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Dr. S. Virtanen, National Public Health Laboratory, Kiinamyllynk 10, 20 520 Turku 52, Finland; Dr. E.-A. Lahikainen, Kauppiaskatu 15 A 3, 20 100 Turku 10, Finland.

S. Virtanen, E.-A. Lahikainen: Bacampicillin in Acute Otitis Media pg/ml ( -+SEM)

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Figure 3: Concentrations of ampicillin in serum and in middle ear effusion after oral administration of 800 mg bacampicillin, Results The aspirated samples of middle ear fluid were purulent in all patients. Concentrations of ampicitlin in middle ear effusions and serum one and twelve hours after a single oral dose of 800 mg bacampicillin are shown in Table 1 and in Figure 3. The concentrations in middle ear effusions were high. T h e m e a n concentration (_+ S E M ) after one h o u r was 2,4 _+ 0.4 gg/ml, 0.3 or m o r e in all samples. T h e m e a n concentrations in middle ear effusions after twelve hours was 0.6 + 0.2 gg/ml, 0.2 gg or more in all samples. The m e a n serum level ( + S E M ) was 7.7 -+ 0.8 gg/ml after one hour and 0.1 -+ 0.03 gg/ml after twelve hours. The m e a n concentration (_+ SEM) b e t w e e n 2 0 - 4 5 minutes was 0.6 + 0.7 ~g/ml in ear effusions and 2.8 +_- 2,3 gg/ml in serum. T h e effect of bacampicillin was rapid. T w e l v e hours after administration, the symptoms and signs of inflammation were decreasing, and in seven of f o u r t e e n patients it was not possible to get a sample from the middle ear by aspiration. Haemophilus influenzae was cultured in one of the cases where the aspirated fluid was taken one h o u r after

Table 1: Concentrations of ampicillin in middle ear effusions and serum after oral administration of 800 mg bacampicillin*.

Number of samples Mean Range S.E.

Middle ear effusion (gg/ml) 1 hour 12 hours 16 7 2.4 0,6 0.3-6.0 0,2-1.5 0.4 0,2

Serum (ptg/ml) 1 hour 12 hours 20 14 7.7 0.1 1.4-16 0-0,35 0.8 0,03

* In six patients samples were taken at different times 20-45 minutes after administration of the drug, and these results are shown in the text.

administration of bacampicillin and the o t h e r samples were negative. Cultures from all aspirated fluids taken twelve hours after administration of the drug were negative, Discussion In the present study the m e a n peak serum level corresponds well to previous results obtained in patients with maxillary sinusitis (5) and in patients with chronic bronchitis (6). It is" somewhat lower than the level registered in healthy volunteers (2, 3). Lahikainen et al. (7) h a v e previously shown that the levels after oral azidocillin and ampiciLlin in middle ear secretions w e r e high after 12 hours and after 8 hours respectively. So far there are n o studies of the concentrations of ampicillin in middle ear effusions after 12 hours. The most problematic of the causative organisms of acute otitis at present is H. influenzae, A b o u t 9 0 % of H. influenzae strains are inhibited by 0.32 gg/ml of ampicillin (8). In the present series the m e a n concentration ( + S E M ) of ampicillin in .middle ear effusions twelve hours after a single dose of bacampicillin was 0.6 + 0.2 t~g/ml. T h e sustained level in middle ear effusions seem to justify the oral administration of 800 mg bacampicillin twice a day in acute otitis media.

Literature 1. Bodin, .IV. 0., EkstrOm, B., Forsgren, U., Jalar, L. P., Magni., L., Ramsay, C., Sj6berg, B.: Bacampicillin: A new orally wellabsorbed derivative of ampicillin. Antimicrob. Agents Chemother. 8 (1975) 518-525. 2. Magni~ L., SjOberg, B., SjOvall, Z, Wessman, J.: Clinical pharmacological studies with bacampicillin: In: Williams, J. D., Geddes, A. M. (ed): Chemotherapy. Plenum Press, New York/London, 1976, p. 109.'

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S. Virtanen, E.-A. Lahikainen: Bacampicillin in Acute Otitis Media 3, Simon, C., Malerczyk, V., Klaus, M.: Absorption of bacampicillin and ampicillin and penetration into body fluids (skin blister fluid, saliva, tears) in healthy volunteers. Scand. J. Infect. Dis. Suppl. 14 (1978) 228-232. 4. Jalling, B., Malmborg, A.-S.. Lindman, A., Bordus, L. 0.: Evaluation of a micromethod for determination of antibiotic concentrations in plasma. Eur. J. Clin. Pharmacol. 4 (1972) 150-157. 5. Raunio, V., Jokinen, K., Karjalainen, S.: Clinical, bacteriological, and pharmacological study of bacampicillin in chronic maxillary sinusitis: In: Williams, J. D., Geddes, A. M. (ed): Chemotherapy. Plenum Press, New York/London, 1976, 151.

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6. Maesen, F. P. V., Beeuwkes, H., Davies, B., L, Buytendijk, /t. J., Brombacher, P. J., Wessman, J.: BacampiciUin in acute exacerbations of chronic bronchitis, a dose-range study. J, Antimicrob. Chemother. 2 (1976) 279-285. 7. Lahikainen, E. A., Vuori, M., Virtanen, S.: Azidocillin and ampicillin concentrations in middle ear effusion. Acta Ototaryngol. (Stockh.) 84 (1977) 227-232. 8. Kamme, C.: Susceptibility in vitro of Haemophilus influenzaeto penicillin G, penicillin V and ampicillin. Acta Pathol. Microbiol. Scand. (B) 75 (1969) 611-621.

Ampicillin concentrations in middle ear effusions in acute otitis media after administration of bacampicillin.

S. Vb:tanen, E . - A . L a h i k a i n e n Ampicillin Concentrations in Middle Ear Effusions in Acute Otitis Media after Administration of Bacampicil...
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