Concentration of azidocillin, erythromycin, doxycycline and clindamycin in dental alveolar serum after single oral doses

Int. J. Oral Surg. 1977: 6:65-74 (Key words: antibiotics; dental extraction; serum concentrations)

Concentration of azidocillin, erythromycin, doxycycline and clindamycin in dental alveolar serum after single oral doses HANS BYSTEDT, ANN DAHLB)kCK AND CARL-ERIK NORD Departnzents o] Oral Surgery and Oral Microbiology, ,Karolinska Institute and National Bacteriological Laboratory, Stockholm, Sweden

Treatment of osteitis in the mandible after surgery is still a clinical problem. Levels of four antibiotics - azidocillin, erythromytin, doxycycline, and elindamycin - were measured in serum and dental alveolar serum in 42 patients undergoing oral surgery. The systemic serum concentrations were higher than the dental alveolar serum concentrations in all patients. The maximal concentration in the alveolar serum for azidocillin was 6.0-12.0 Ixg/ml, for erythromytin 0.7-1.3 ~tg/ml, for doxycycline 2.8-3.6 ~tg/ml, and for clindamycin 2.0-2.8 ixg/ml. When the dental alveolar serum concentrations of the various antibiotics were related to their range of inhibitory concentrations for microorganisms isolated from mandibular osteitis, it was noticed that each drug achieved levels sufficient to inhibit most strains. ABSTRACT

- -

(Received Jor publication 6 June, accepted 15 August 1976)

In the treatment of bacterial infections, adequate antibiotic concentrations must be obtained at the site of infection. It was believed earlier that this could be expected if the antibiotic in serum was higher than the m i n i m u m inhibitory concentration for the bacteria causing the infection. However, it has become obvious during the last few years that serum concentration is not always equal t o the concentration in the tissue. Thus, t h e ratio between the antibiotic concentration in the tissue and the minimum inhibitory concentration of the infecting bacteria is a better index for the therapeu-

tic effect than the ratio between serum level and minimum inhibitory concentration. Treatment of osteitis (osteomyelitis) in the mandible after extraction of a tooth is still a clinical problem. There are many reports on local antibiotic therapy of mandibular infections12, ~, 2~, but only a few authors have determined the antibiotic concentration in the mandible after systemic use. Thus OIKARINEN ~; MALMSTROM~tl studied the concentrations of phenoximethyipenicillin in the capillary blood in the m a n d i n e and compared these results with those in the serum and recently Nom32a found

66

BYSTEDT, DAHLB.X,CK A N D N O R D

cephalexine concentration in m a n d i b u l a r b o n e after o r a l administration of the drug. T h e p u r p o s e of t h e present investigation was to d e t e r m i n e h o w the concentration of azidocillin, erythromycin, doxycycline, and clindamycin in dental alveolar serum is related to t h e magnitude and duration of the s e r u m concentration. The m i n i m u m inhibitory c o n c e n t r a t i o n of bacteria isolated f r o m m a n d i b u l a r infections was also determ i n e d and c o m p a r e d with achievable concentrations o f the antibiotics in the dental alveolar serum. Azidocillin, erythromycin, doxycycline, and clindamycin were chosen as test antibiotics since they are c o m m o n l y used in the t r e a t m e n t of oral infections.

Material and methods Patients and drug administration - Forty-two

patients, 24 women and 18 men, between 18 and 44 years of age, participated in this investigation. All of them had been admitted during 1975 to the Department of Oral Surgery, Huddinge Hospital for surgical removal of an impacted third molar in the mandible. The operation was carried out under under lidocaine-adrenaline conduction anesthesia (Xylocaine-Exadrin| 2 %, Astra, Sweden). No operations were performed during an acute stage of inflammation. The patients received no premedication. Before operation, all patients were given a single oral dose of antibiotic on an empty stomach. Ten patients were given azidocillin 750 mg (Olobacillin| Astra, Shderfiilje, Sweden), 12 patients erythromycin 500 mg (Reciomycin| Kabi, Stockholm, Sweden), 10 patients dexycye!ine 200 mg (Vibramyein| Pfizer, New York, USA), and 10 patients clindamycin 300 mg (Dalacina| Upiohn, Kalamazoo, USA). No other drugs were administered during the study or for at least 48 hours before it. Sampling procedure - Capillary blood from the finger tip (systemic serum sample) was colIected in heparinized hematoerit tubes before the first administration of the drug at the operation and after 30, 60, 90, 120, 180, and 240 min. A sample of capillary blood ia the mandible (dental alveolar serum sample) was taken by the same technique simultaneously

with each ffilger blood sample, except at the start of the operation. The centrifugation of the tubes was performed at once, and the plasma was removed immediately after the centrifugation for determination of the drug, either the same day or later after storage at -20~ Assay of antibiotics- The concentration of the four different antibiotics was determined by the agar diffusion method with freshly prepared paper disks as diffusion centers 1~ Bacto Penassay Seed agar@ (Difco) was used as test medium. The test strains were Sarcina lutea ATCC 9341 for azidociUin, erythromycin, and elindamycin and Bacillus cereus A T C C 11778 for doxycycline. Pooled human plasma was used for the standard series when assaying the antibiotic contents in the samples. Bacterial s t r a i n s - 198 bacterial isolates obtained from mandibular infections in 169 patients during 1 year were investigated. The strains were selected so that two strains never originated from the same patient. Subcultures of the strains were made at the time of isolation and stored at --70~ *. Identification of streptococci was based on biochemical and serological reaetionsL Anaerobic bacteria were identified by biochemical reactions and gas chromatographic analysis of metabolic productsl,. Determination o/ minimum inhibitory concentrations - T h e agar dilution method of

ERICSSON & SttgltlllS a was used. Stock solutions of each drug were prepared in sodium phosphate buffer (pH 7.2) at concentrations 10 times higher than the ones used in the agar. The following antibiotics were tested: D-azidobenzylpenicillin sodium salt batch 29 (azidoeillin, Astra, Stiderfiilje, Sweden), erythromycin stearate lot no. 29-006-VI (erythromycin, Kabi, Stockholm, Sweden), doxycycline hydrochloride lot no. 103-58704 (doxycycline, Pfizer, Brussels, Belgium) and clindamycin hydrochloride lot no. A8012 (clindamycin, Upjohn, Kalamazoo, MI, USA). The antibacterial sensitivity tests were made on PDM antibiotic sensitivity medium (lot 12) supplied by Biodisk, Solna, Sweden. The composition of the medium has recently been described 8~ Two ml of the stock solution was added to 18 ml of the melted agar. The agar was mixed, poured into a 9-cm Patti dish and allowed to set. Samples of the bacterial cultures were transferred to cups arranged to the 32 prongs in a Steers replicator ~8. Each plate was then spot-inoculated and incubated for 24 h at 37~ in Gas Pak anaerobic

CONCENTRATION OF ANTIBIOTICS AFTER ORAL DOSAGE

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Fig. Z Concentration of azidocillin (mean values and s.d.) in serum I - e and dental alveolar serum O - O from 10 subjects after a single oral dose of 750 mg.

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180

Fig. 2. Concentration of erythromyein (mean values and s.d.) in serum Q - # and dentaI alveolar serum O - O from I0 subjects after a single oral dose of 500 mg.

jars (BBL, Maryland, USA). The minimum inhibitory concentration was defined as the lowest concentration of the antibiotic inhibiting growth.

dental alveolar serum concentrations w e r e obtained after 90 rain. The dental alveolar serum concentration followed the systemic serum concentration but was about 0.5 Fg/ml lower. Th e serum levels of erythromytin were also found to vary within a w i d e range. D o x y c y c I i n e - I n all patients receiving a

Results A z i d o e i l l i n - T e n patients received a single oral dose of 750 m g azidocitlin. As shown in Fig. I the individual variations of the penicillin concentration were wide both in serum samples and in dental alveolar serum samples, The maximal penicillin concentration in the serum sample was observed 30-60 min after the intake, while the highest concentration in the dental alveolar serum sample was noticed 3090 min after. The alveolar serum concentration followed the systemic serum concentration very closely during the entire period studied and was still more than 5 ~tg/ml after 180 rain. The alveolar serum concentration followed also closely the systemic serum concentration in the individual patient. E r y t h r o m y c i n - T h e serum concentrations of erythromycin in 10 patients are presented in Fig. 2. Two patients did not attain any measurable level of erythromycin. The maximal systemic serum concentrations and the

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68

BYSTEDT, DAHLB.~.CK AND NORD

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Table 1. Bacteria isolated from mandibular osteitis in 169 patients

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180

MINUTES AFTER INTAKE Fig. 4. Concentration of clindamycin (mean values and s.d.) in serum O - e and dental alveolar serum O - O from 10 subjects after a single oral dose of 300 mg,

single dose of doxycycline, a maximal systemic serum concentration of 4.4 ~g/ml with a range of 1.9-6.6 ~tg/ml was noticed after 3 hours (Fig. 3). The maximal concentration in the dental alveolar serum was also obtained after 3 hours and was about 1.0 btg/ml lower than the systemic serum concentration. C l i n d a m y c i n - The clindamycin concentrations in serum samples and dental alveolar serum samples varied greatly in the patients investigated (Fig. 4). A peak in serum was seen after 90 rain, while the corresponding peak in alveolar serum was not noticed until after 2 hours. The mean concentration in the serum was 2.8 btg/ml with a range of 1.5-5.0 ~tg/ml and the mean concentration in the alveolar blood was 2.4 ~tg/ml with a range of 1.7-3.4 ~xg/ml. M i n i m u m inhibitory concentrations o] the isolated b a c t e r i a - M o s t of the bacteria isolated from mandibular osteitis were typed as alphastreptococci (Table 1). I n this bacterial group Streptococcus mitior dominated, while rather few strains identi-

No. of strains 97

A l/astreptococci S, mitior S. mutans S, sat,guis

55 7 35

Peptostreptocoeei P. micros P. parvulus P. productus

14 2 5

Peptococci P. asacharolyticus P. constellatus P. magnus P. prevotii P. sacharolytieus P. variabiiis

6 3 9 3 2 1

Bacteroides B. amylophilus B. clostridiformis B. coagtllans B. corrodens B. ]ragilix B. /urcosus B. oralis B. pneztmoshztes B. succinogenes

2 1 2 2 5 1 4 4 1

Fusobacteria F. aquatile F. bullosurn F. ]usiforme F. mortif erurn F. neerophorurn F. nucteatum F. plauti F. prausnitznii F. varium

9 2 2 2 2 3 1 2 6

Leptotricia L. buccalis

5

21

24

22

29

5

fled as Streptococcus m u t a n s were recovered. Among the anaerobes the genera of Peptococcus, Peptostreptococcus, Bacteroides, Fusobacterium and Leptotricia were found and 28 different bacterial species were recognized. Most strains were sensitive to azidocillin and only a few strains showed minimum

CONCENTRATION OF ANTIBIOTICS AFTER ORAL DOSAGE

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MINIHUH INHIBITORY CONCENTRATION (/Jg/mt)

Fig. 5. Minimum inhibitory concentration in Fg/ml of azidocillin for 198 bacteria isolated from mandibular infections.

inhibitory concentration values over 2.0 ~tg/ml (Fig. 5). The antibiotic sensitivity to erythromycin is shown in Fig. 6. Only a small number of strains belonging to Bacteroides, Fusobacterium, and Leptothrichia were resistant (MIC > 8 . 0 gg/ml). Twelve of 97 alphastreptococei and six anaerobes showed minimum inhibitory

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Fig. 7, Minimum inhibitory concentration in ~tg/ml of doxycycline for 198 bacteria isolated from mandibular infections.

concentrations of m o r e than 8 btg/ml for doxycycline (Fig. 7). Only a few isolates were found to b e resistant to clindamycin (MIC ~>4.0 gg/ml), while most strains were sensitive ( M I C values 0.004-1.0 ~tg/ml) (Fig. 8).

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Fig. 6. Minimum inhibitory concentration in btg/ml of erythromycin for 198 bacteria isolated from mandibular infections.

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Fig. 8. Minimum inhibitory concentration in ~tg]ml of clindamycin for 198 bacteria isolated from mandibular infections,

70

BYSTEDT, DAHLBNCK AND NORD

Table 2. Peak dental alveolar serum concentrations and minimum inhibiting concentrations (gg/mI) Azidoefllin

Erythromycin

Doxycycline

Clindamycin

3.4-16,5 9.1

0.5-2.8 0.9

1,9-6.6 3.3

1,7-3.4 2.4

Peak alveolar serum levels range mean

Minimum inhibitory concentrations

Alphastreptococci Peptostreptococci Peptococci Bacteroides Fusobacterla Leptotricia

Range

Mean

Range

0.004-0.5

0 . 0 0 5 0,016-1.0

Mean

Range

Mean

Range

Mean 0.96

1,8

0.004-16.0

0.004-0.:1.250 . 0 6

0.122 0.004>/16.0 0.004--0.5 0 . 1 7 0.004-0.5

0.14

0.004-0,125 0.04

0.004-8.0 0.4 0.004--4.0 0.8 0.004-16,0 1.2 0.004--0.1250 . 0 6

0.004-2.0 0.004-16.0 0.004-16.0 0.016--8.0

1.0 0.8 1,5 0.23

0.004--1.0 0.2 0.004--0,1250.016 0.004-16,0 1.3 0.004-0,032 0,02

The relationship between the minimum inhibitory concentrations for the isolated bacteria and the maximal concentration of the antibiotics tested in the dental alveolar serum is given in Table 2. It can be seen that each antibiotic achieves concentrations in serum which are inhibitory in vitro for most strains but not for all.

Discussion Successful treatment of oral infections presupposes the use of the proper antibiotic in adequate doses. Phenoximethylpenicillin is the first drug of choice since it has a bactericidal effect and low toxicity~. In our study, azidocillin was taken in the fasting state to avoid variations in the serum concentration, since it is well known that the food contents in the stomach may influence the concentration in the serum when oral administration is used. Variations in serum concentration also lead to variations in tissue concentrations which are of importance in the treatment of infections in the soft tissues as well as in bone.

0.5 1.4 6,9 3.6

0.004-16.0 0.004-16.0 0,004-16.0 0,008-0,125

With large oraI doses of penicillin, individual variations in adsorption become of less clinical importance. A higher dosage is also needed when oral administration is used in the treatment of severe infections in the jaws such as osteomyelit[s. I n these cases the circulation may not p e r m i t an adequate tissue concentration with lower doses of the antibiotic. Therefore in this investigation an oral penicillin, azidocillin, which was reported to give high serum concentration during a long period tested, was used2~. When azidocillin was administered, maximal concentrations were obtained in the serum already within 60 rain and the values exceeded the minimum inhibitory concentration of bacteria isolated from oral infections. A n analysis of the concentration findings in the patients showed t h a t the concentration in the dental alveolar serum was at least 10 times higher than the minim u m inhibitory concentration for the microorganisms isolated from oral infectionsl7, 24. Thus, normal dosage of azidocillin can be expected to give adequate antibacterial con.

CONCENTRATION OF ANTIBIOTICS AFTER ORAL DOSAGE centrations in the operation region. Penicillin concentrations, far above minimum inhibitory concentration of bacteria isolated from the oral cavity, were observed soon after the intake, i.e. in 30 rain. The correct time for prophylactic antibiotic treatment with penicillin should therefore be 1 hour before the operation so that the maximum penicillin concentration in the alveolar serum after the first dose is reached at the time of the operation 10. Thereby, the operation region will be irrigated by blood containing penicillin and the blood clot formed in the wound cavity will also have a penicillin activity for at least 48 hours10. Many clinically important oral bacteria are susceptible to achieved levels of azidocillin. Anaerobes associated with the oral flora, such as anaerobic cocci and Gramnegative rods, are examples of susceptible strains such as were tested in our investigation. These bacteria together with alphastreptococci are responsible for most oral infections. An exception from this pattern is Bacteroides fragilis: a major percentage of these strains are resistant to penicillinS because this species contains ~-lactamase, an enzyme that destroys penicillin27. Fortunately, this Bacteroides species is not as often isolated from oral infections as other Bacteroides species which, in contrast to B. fragilis, are sensitive to penicillin zs. Erythromyein is a second choice in patients sensitive to penicillins. However, staphylococci and many other bacterial species can readily develop resistance to erythromyein in vitro~q Increased resistance is not often observed during short-term treatment, but is common during prolonged treatmentS1. The acid lability of erythromycin base makes it necessary to administrate the antibiotic in a form giving protection from gastric acid. We used tablets of erythromytin stearate, resistant to the gastric acid and broken down in the intestine liberating

71

the erythromycin base. After a single dose of 500 mg erythromycin, the systemic serum level rose to 1.0-1.5 ~tg/ml within 2 hours. However, there were some individual variations, and in two subjects no adequate levels whatever were attained. About 10 % of the anaerobic bacteria isolated from oral infections were found to have minimum inhibitory concentration values higher than 1.0 Ixg/ml, while most alphastreptococci from oral infections have values lower than 0.5 p.g/ml. This is important to keep in mind when treating oral infections with erythromycin. Thus, bacteria isolated from oral infections display a varying degree of sensitivity to erythromycin. The oral route is often used because of the difficulty in admirtistering the drug parenterally. However, as shown in our results, relatively iow serum levels are achieved. About 80 % of anaerobic streptococci, fusobacteria, and baeteroides are sensitive to easily achievable levels by oral administration. Definitive clinical studies to document the efficacy of therapy in patients with sensitive strains are not yet available. Erythromyein penetrates bone less efficiently than tetracyelines and lincomyein is, but in spite of this, erythromycin has been fotmd useful in the treatment of osteomyelitis~0. However, in the treatment of osteitis it is preferable to use bactericidal antibiotics instead of bacteriostatic ones. The maximal concentration in the alveolar serum was found 90 rain after intake. This means that the antibiotic treatment should start about 2 hours before operation. Tetracyelines also provide an alternative to penicillin for treatment of oral infections. Several new tetracyclines have been introduced during the last few years and we wanted to test one of these new drugs since they differ in pharmaeokineties from the earlier tetracyclines. Doxycycline was chosen in this investigation since this drug has been successfully used in the treatment both of

72

BYSTEDT, DAHLB*CK AND NORD

sinusifi# and respiratory tract infections 21. Both the maximal systemic serum concentration and the maximal alveolar serum concentration were noted 3 hours after the intake. The antibiotic concentration in the alveolus exceeded the minimum inhibitory concentrations for most bacteria more than fivefold. Doxycycline can penetrate even poorly vascularized tissues due to its optimal lipid solubility which facilitates transport across biological membranes, contrasting to watersoluble antibiotics such as penicillins. This property in pharmacokinetics makes doxycycline a suitable drug for treatment of purulent oral infections. Another advantage of this drug is that only one daily dose is needed due to its slow excretion. The tetracycline class of antibiotics has been regarded as the agent of choice for infections caused b y anaerobes. However, recent studies have shown a high resistance particularly by Bacteroides [ragilisS. The incidence of resistant strains varies, between 40 and 50 % of clinical isolates. In our study only five strains of B. fragilis were isolated, however. Tetraeyctines are valuable in oral infections b u t a prophylactic administration should be avoided in cases where a bactericidal effect is essential. Therefore tetracyclines have no place in the prophylactic treatment in patients with bacterial endocarditis. Clindamycin, an analogue of lincomycin, possesses an antibacterial spectrum similar to lincomycin, but it is more active than lincomycin in vitro both against anaerobes ~-0 and streptococci11. The efficacy of this drug for therapy of anaerobic infections s as well as streptococcal infections 2 is well documented. Clindamycin treatment of osteomyelitis has been reported to be successful by several authors7, sn reflecting the high bone concentrations o f clindamycin achieved 2-*.

Clindamycin has a good activity against streptococci and anaerobes including B, [ragiIis, a n d over 95 % of clinical isolates from oral infections are susceptible to levels of cliadamycin achievable at recommended doses. Clindamycin has been successfully used in oral infections including osteomyelitis82. A limitation to the use of clindamycin is the occurrence of enterocolitis is. This has been observed both with oral and parenteral therapy and should be noted carefully when giving this drug. The lower concentrations of erythromytin, doxycycline, and clindamycin in the dental alveolar serum compared with those in the systemic serum m a y . b e due to the effect of lidocahae-adrenaline conduction anesthesia and will be further investigated. In the mandibular osteitis, the ability of antibiotics to penetrate bone is probably essential. In a further study the relationship between antibiotic concentration in dental alveolar serum and mandibular bone will be investigated.

References 1. COWAN, S.T. & STEEL, K.J.: Manual /or the identification o/ medical bacteria. University Press, Cambridge 1974. 2. DILLON, H. C. & DEmucx, C. W.: Clinical experience with clindamycin hydrochloride: 1. Treatment of streptococcal and mixed streptococcal-staphylococcal skin infections. Pediatrics 1975: 55: 205-212, 3. Doarmusc~, K., Nomp, C. E. & W~DSTg~SM, T.: Biochemical characterization and in vitro determination of antibiotic susceptibility of clinical isolates of Bacteroides /ragilis. Scand. J. ln/ect. Dis. 1974: 6: 253-258. 4. DOWBLL, V. g. & HAWKINS, T. M.: Laboratory methods in anaerobic bacteriology. Center for Disease Control, Atlanta 1968. 5. ENEROTH, C. M., LUNDBERG, C. & Wll2gTLIND, B.: Antibiotic concentrations in maxillary sinus secretions and in the sinus mueosa. Chemotherapy 1975: 21: 1-7. 6. ExlcSSO~, H. M. & SI~VauUs, J. C.: Anti-

C O N C E N T R A T I O N O F ANTIBIOTICS A F T E R ORAL DOSAGE

73

biotic sensitivity testing. Report of an inG.: Penicillin treatment in oral surgery in patients with coagulation disorders. Int. Y. ternational collaborative study. Aeta Pathol. Oral Surg. I975: 4; 198-2fl4. MicrobioL Scand. (B) 1971: Suppl. 217. 20, M~T1N, W. J., GARDWaY., M. & W.~snrN~7. FEIG:IN, R. D., PICK..ER/NG, L. K,, A ~ X R WON, J. A., II: In vitro antimicrobial susSON. D., I(~EN'EY, R. E. & SHACKLEFORD, ceptibility of anaerobic bacteria isolated P, G.: Clindamycin treatment of osteofrom clinical specimens. Antimicrob. Agents myelitis and septic arthritis in children. Chemother. 1972: 1:148 158. Pediatrics 1975: 55: 213-223. 21. MEIER, J.: Doxycycline in respiratory tract 8. F1NEOOLD, S, M.: Antimicrobial therapy infections. Chemotherapy 1975: 21: 130of anaerobic infections. Postgrad. Med. 135. 1975: 58: 72-78. 22. NICHOLS, P., ME'n~RS, B. R., LEVY, R. N. 9. GxaxoI~, L. P., LAMBERT, H. P. & & HmSCmaAN, S. Z.: Concentration of O'GRADY, F.: Antibiotic and chemotherapy, clindamycin in human bone. Antimicrob. 4th ed. Churchill Livingstone, Edinburgh Agents Chemother. 1975: 8: 220-221. 1973. 23. NORD, C. E.: Distribution of cephalexin 10. GARROD, L. P. & WATERWORTH, P. M.: in the mandible. Cephalosporins: dimenThe risks of dental extraction during sions and /uture. Excerpta Medica, A m penicillin treatment. Br. Heart J. 1962: 24: sterdam 1974, p. 85-86. 39--46. 24. NORD, C. E. & WAI3ST~SM, T.: Suscepti11. GEDDES, A. M., BRIDGEWATER, F. A., bility of haemolytic oral enterococci to WIt_LIAMS, D. H., CON, J. & GRINSHAW, eight antibiotics in vivo. Acta OdontoL G, 1.: Clinical and bacteriological studies Scan& 1973: 31: 395-399. with clindamycin. Br. Med. J. 1970: 2: 25. NOB.DENKAM,A., SYDNE$, O. ~: GD~GAARD, 703-704. I.: B a c i t r a c i n - neomycin in impacted 12. GOLDMAN, D, R,, KILGORE, D, S., PANZER, mandibular third molar sockets. Int. J. J. D. P-' ATKINSON, W. H.: Prevention of Oral Surg, 1973: 2: 279-283. dry socket by local application of lincomycin in Gelfoam. Oral Surg. 1973: 35: 47226. OtKA~INEN, V. I. & MALMSTR6M, M.: 474. Penicillin V concentration in dental alveolar 13. GI~ADY, J. E. & STERN, K. F.: Penetration blood after tooth extraction. Seand. J. of tir~eomycirl into bone. Antibi~t. Che~oDent. Res. 1972: 80: 279284. ther. 1965: 9: 201-205. 2% OLSSGN,B., NORD, C. E. & WADSTR6M,T.: 14. HALL, H. D,, BILDMAN, B. S. & HAND, Formation of [3-]actamase in Bacteroides C. D.: Prevention of dry socket with local ]ragflis: cellbound and extraeellular activity. application of tetracycline. J. Oral Surg. Antimicrob. Agents Chemother. 1976: 9: 1971: 29: 35-37, 727-735. 15. H O L D ~ ' ~ , L. V. & MOORE, W. E. C.: 28. QUAYLE, A. A.: Bacteroides infections in Anaerobe laboratory manual, 2nd ed. Viroral surgery. J. Oral Surg. 1974: 32: 91-99. ginia Polytechnic Institute and State Uni29. RAMSAY, C. H., BODm, N. O, & I-I,~NSSON, versity, Blacksburg, Virginia 1973. E.: Absorption, distribution, biotransforma16, JALLI~O, B., MALMBORO, A. S., LINDMAN, tion and excretion of azidocillin - a new A. & Bol~us, L. O.: Evaluation of a semi-synthetic penicillin - in mice, rats and micromethod for determination of antidogs. Arzneimittel-Forsch. 1972: 22: 1962biotic concentrations in plasma. Europ. J. ] 970. Clin. PharmacoL 1972: 4: 150-]57. 30. REGE, S. R., SHAH, K. L, & ~V[ARFATIA, P. T.: Osteomyelitis of maxilla with extru17. JOKINEN, K. & RAUNIo, V.: Penetration of sion of teeth in the flow of the nose reazidocillin into the secretion and tissues in quiring extraction. J. Laryng. 1970: 84: chronic maxillary sinusitis and tonsillitis. 533-535. Acta Otolaryngol. 1975: 79: 460-465. 31. SANDERS, E., FOSTER, M. T. & Sco'rr, D.: 18. LEFRocK, J. L., KLAINER, A. S., CHEN, S., Group A betahemolytic streptococci resisGARNER, R, B., O M ~ , M. & Ar~ERSO~, tant to erythromycin and lincomycin. N e w W.: The spectrum of colitis associated with Engl. J. Med. 1968: 278: 538-540. lincomycin and clindamycin therapy, d. ln32. SClaUEN, N, I., PANZER, J. D. & A r m s [ect. Dis. 1975: 131.: 108-115. SON, W. H,: A comparison of clindamycin 19. LUNDBERO, C., NORD, C. E. & RAMSTR~M,

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BYSTEDT, D A H L B A C K AND NORD

and penicillin in the treatment of oral infections. I. Oral Sure,. 1974: 32: 503-505. 33. STEERS, E., FoL'rz, E. L., GRAVES, B. S. & RIDER, J.: An inocula replicating apparatus for routine testing of bacterial susceptibility to antibiotics. Antlbiot. Chemother. 1959: 9: 307. 34. Wr.AV~R, J. R. & PATr~e, P. A.: Inducible resistance to erythromycin in Staphylococcus aureus. J. Bacteriol. 1964: 88: 574-580.

Address: Hans Bysredt Department o] Oral Surgery School o / D e n t i s t r y Karolinska Institute Fack S-14104 Huddinge Sweden

35. WaXRTON, M. R. & BBDDOW,F. H.: Clindamycin for acute osteomyelitis hi children. Postgrad. Med. J. 1975: 51: 166-168. 36. WKeTL,tND, B., NOR.D, C. E. & WA~Sa'atiSM, T.: In vitro sensitivity of isolates of Pseudomonas aeruginosa to carbenieillin, gentamicin, tobramycin and some other antibiotics. Scand. J. ln]e'ct. Dis. 1974: 6: 4952.