Article

Vol. 11. No. 12

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Eur. J. Clin, Microbiol. Infect. Dis., December 1992, p. 1129-1136 0934-9723/92/12 01129-07 $3.00/0

Clindamycin versus Phenoxymethylpenicillin in the Treatment of Acute Orofacial Infections

L. v o n K o n o w 1, Elk, K 6 n d e l l 1, C.E. N o r d 2,3., A. H e i m d a h l 1

The efficacy of clindamycin and phenoxymethylpenicillin in the treatment of orofacial infections was compared in a randomised study in 60 patients: 30 patients received clindamycin 150 mg every 6 h for seven days, and 30 received phenoxymethylpenicillin 1 g every 12 h for seven days. Where indicated incision and drainage were carried out. All patients but one in each group responded satisfactorily to treatment. Although the clindamycin group had a shorter duration of pain, swelling and fever and more favourable laboratory findings, the differences between the groups were not statistically significant. Of the 60 microbiological specimens 23 yielded only anaerobic bacteria, 34 both anaerobic and aerobic bacteria, two aerobic bacteria only and one no growth. In the penicillin group one case of severe diarrhoea occurred, and six patients in the clindamycin group had moderate to severe gastrointestinal discomfort, including one case of Clostridium difficile associated diarrhoea. This difference was however not statistically significant. The results support the continued use of penicillin for treatment of orofacial infections, with clindamycin serving as an effective alternative.

Anaerobic bacteria play a dominant role in a variety of human infections (1), and are the major pathogens in orofacial infections (2-5). Although penicillin has long been the drug of choice for the treatment of orofacial infections, clinical failures in cases involving penicillin-resistant beta-lactamase-producing Bacteroides species have been reported (6-9). Beta-lactamase producing Bacteroides species occur frequently in the oral cavity, especially subsequent to penicillin therapy (10). With increasing use of antimicrobial agents, orofacial infections caused by penicillinresistant Bacteroides strains may be expected to become more frequent. In vitro, virtually all strictly anaerobic strains, including penicillinresistant species isolated from orofacial infections, are highly sensitive to for instance clindamycin and nitroimidazoles (6, 3). These agents are potential alternatives to penicillin for treatment of orofacial infections caused by penicillinresistant anaerobic bacteria. Nitroimidazoles are less often associated with adverse gastrointestinal effects than clindamycin (11, 12). However, in patients with a risk of endocarditis or in patients i Department of Oral Surgery and ZDepartment of Microbiology, Huddinge University Hospital, Karolinska Institute, S-141 86 Huddinge, Sweden. 3National Bacteriological Laboratory, Stockholm, Sweden.

suffering from immunodeficiency, the use of nitroimidazoles may be contra-indicated because of their limited activity against viridans streptococci (13, 14). The aim of the present study was to compare penicillin and clindamycin with respect to microbiological and clinical efficacy and adverse effects in the treatment of orofacial infections.

Materials and Methods Patients. Sixty patients (36 males and 24 females, mean age 46 years, range 20-70 years) presenting at the Department of Oral Surgery, Huddinge University Hospital, Karolinska Institute, with acute orofacial infections of dentoalveolar origin of less than one week's duration participated in the trial. The spectrum of infections included periapical (most common), periodontal and postoperative infections after dentoalveolar surgery, with or without spread into orofacial spaces. None of the patients had received any antimicrobial agents during the preceding two months. Antimicrobial Therapy. Patients were allocated at random, using Doeumenta Geigy's randomising tables, to receive treatment with phenoxymethylpenicillin tablets (Leo AB, Sweden) I g q 12 h for seven days or clindamycin tablets (Upjohn, USA) 150 mg q 6 h for seven days. All patients except one in the penicillin group and three in the clindamycin group were treated surgically

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Eur. J. Clin. Microbiol. Infect. Dis.

with drainage. These four patients received antibiotic therapy only. All patients were examined on days 1, 3, 7 and 14 by the same surgeon. Patient compliance was monitored by tablet counts on days 3 and 7 and by collecting blood samples at all visits to assay serum concentrations of penicillin and clindamycin. The clinical course of the infection was foUowed by documenting the presence and severity of fever, swelling, pain and disturbance of sleep. The response to treatment was regarded as poor when clinical symptoms had not disappeared or markedly subsided within five days, or when symptoms recurred during the observation period (15). Patients were urged to report immediately any sign of gastrointestinal disorder or other discomfort.

MIC > 1 mg/l and clindamycin resistance at an MIC > 4 mg/l (18).

Clinical Laboratory Investigations. Blood samples were

in a c c o r d a n c e with instructions as r e v e a l e d b y the antibiotic c o n c e n t r a t i o n s a s s a y e d at all visits.

Statistical Analysis. Differences in efficacy between the two treatment groups were analysed by Mann-Whitney's U-test and differences in adverse effects by Fisher's twotailed exact test.

Results

Patient Compliance. All p a t i e n t s t o o k t h e tablets

collected on days 1 and 14 for determining the haemoglobin level, erythrocyte sedimentation rate, total white blood cell count, and SGOT, SGPT and alkaline phosphatase levels. On days 1, 3, 7 and 14, blood was drawn from the finger tip to determine the serum concentration of penicillin and clindamycin respectively.

Clinical Outcome. T h r e e p a t i e n t s in the penicillin g r o u p d i s c o n t i n u e d t r e a t m e n t , o n e b e c a u s e of d i a r r h o e a , o n e b e c a u s e o f t h e distance to the clinic a n d o n e f o r u n k n o w n reasons. T w o p a t i e n t s in the c l i n d a m y c i n g r o u p d i s c o n t i n u e d t r e a t m e n t before day 3 because of diarrhoea. The treatment r e s p o n s e was satisfactory in all o t h e r p a t i e n t s except f o r o n e in each group. T h e p a t i e n t in the penicillin g r o u p h a d an abscess originating f r o m an infected residual cyst in the u p p e r d e n t a l alveolar process, and the p a t i e n t in the clindamycin g r o u p had a periapical abscess originating f r o m an u p p e r canine. O n day 7 b o t h patients still d e m o n s t r a t e d swelling, fever a n d p r e s e n c e o f p u r u l e n t material in spite o f r e p e a t e d incisions. S u b s e q u e n t to incision o n day 7 b o t h infections subsided within a few days. C o m p a r e d to the penicillin g r o u p the d u r a t i o n o f pain, swelling a n d fever was less in the c l i n d a m y c i n g r o u p and the l a b o r a t o r y findings also t e n d e d to b e m o r e favourable, b u t the differences w e r e n o t statistically significant ( M a n n - W h i t n e y ' s U-test). T h e data are s h o w n in Table 1.

Microbiological Investigations. On day 1 a specimen of pus was aspirated through intact mucosa or skin after disinfection. The syringes were sealed with a sterile butyl rubber stopper and transported immediately to the microbiological laboratory. The samples were immediately inoculated onto solid and into liquid media and incubated aerobically and anaerobically for up to ten days. The anaerobic media were manipulated in an anaerobic chamber (Coy, USA). Aerobic and anaerobic bacteria were identified morphologically, biochemically and by gas liquid chromatographic analysis of metabolic end-products, as described by Lennette et al. (16). Faecal specimens from patients with diarrhoea were assayed for Clostridium difficile and its toxins as described by Aronsson et al. (11).

Susceptibility Testing. The minimum inhibitory concentrations (MIC) of phenoxymethylpenicillin and dindamycin for the different bacterial strains were determined by the agar dilution method (17, 18), using PDMAntibiotic Sensitivity Medium (BioDisk, Sweden). Agar plates containing doubling concentrations from 0.008 to 64 mg/I of phenoxymethylpenicillin and clindamycin were inoculated with the different bacterial isolates. Aerobically incubated plates were read after incubation for 24 h. Anaerobic plates were incubated at 37 °C in anaerobic jars (GasPak; BBL, USA) and read after 48 h. Penicillin resistance was considered to be present at an

Clinical Laboratory Tests. With r e s p e c t to the e r y t h r o c y t e s e d i m e n t a t i o n rate and total white b l o o d cell c o u n t t h e r e were n o differences between the two g r o u p s during t r e a t m e n t . N o n e o f

Table 1: Duration of pain, swelling, sleep disturbance and fever (temperature 37.5 *C or above) in the two patient groups. Duration (days) in penicillin group Symptom

Total

Median

Pain

63

2

Swelling

83

Sleep disturbance Fever

Range

Duration (days) in clindamycin group Total

Median

Range

0- 7

49

2

1- 4

3

0-14

75

2

0-14

29

1

0- 4

22

1

0- 3

38

1

0- 9

23

0

0- 6

Vo1.11,1992

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Table 2: Number of aerobic and anaerobic organisms isolated from 59 specimens from patients in the penicillin and elindamycin groups. Organisms

Penicillin group

Clindamycin group

Gram-positive cocci Staphylococcus epidermidis Staphylococcus sap rophyticus Streptococcus milleri Streptococcus mitior Streptococcus spp. Micrococcus spp.

1 3

3 1

14

4

9

9

3 1

4 0

Gram-negative cocci

0

1

Gram-positive rods

0

1

Haernophilus influenzae Haernophilus parainfluenzae

3 0

0 2

Other

1

4

35

29

6 8

0 8

1 12 3

2 15 3

2

3

2 0

1 1

0

1

12

7

1 2 0

1 2 3

0

1

Gram-negative rods

Total number of aerobic isolates Gram-positive cocci Streptococcus constellatus Streptococcus intermedius Streptococcus spp. Peptostreptococcus micros Peptostreptococcus spp.

Gram-negative cocci Veillonella parvula Veillonella spp.

Other Gram-positive sporeforming rods Gram-positive non-sporeforming rods Eubacterium Lactobacillus fermentum LactobaciUus ptantarum Actinomyces odontolyticus

Other Gram-negative rods Bacteroides asaccharolyticus Bacteroides corrodens Bacteroides ruminicola Bacteroides ureolyticus Bacteroides spp. Eikenella corrodens Fusobacterium nucleatum Fusobacterium spp.

2 0 8 1

2 4 8 4

19

28

3

0

10 13

8 11

Total number of anaerobic isolates

107

t13

the patients showed abnormal levels of haemoglobin, SGOT, S G P T or alkaline phosphatases at any time during the study. Serum concentrations of penicillin and clindamycin indicated good patient compliance.

Microbiological Findings. Twenty-three speci-

mens contained exclusively anaerobic bacteria, while 34 yielded anaerobic and aerobic bacteria. In two specimens only aerobic bacteria were found and no microorganisms could be detected

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Eur. J. Clin. Microbiol. Infect. Dis.

100 -

80' a~

._=

"6

60'

40 rl

C7

20 ¸

n A i



i

4 mg/l) isolated in the two treatment groups, MIC (rag/l) Patient no.

Organism

Antibiotic treatment

Penicillin

Ciindamyein

4

Bacteroides ureolyticus

clindamycin

6

Eikenella corrodens Veillonella parvula Bacteroides ureolyticus

penicillin

0.064 2

clindamycin

2

0.064

8

Fusobacterium nucleatum Bacteroides corrodens

clindamycin

1 2

0,064 0,125

9

Bacteroides rumin&ola Veillonella parvula

penicillin

16 4

< 0.008 0.032

I2

Fusobacterium nucleatum

penicillin

2

0.016

13

Bacteroides ureolyticus

clindamycin

16

0.125

14

Bacteroides sp.

clindamycin

2

0.064

15

Peptostreptococcusmicros

penicillin

1

0.125

16

Veillondla parvula Bacteroides sp.

penicillin

1

0.125

clindamycin

1

0.125

24

Eubacterium sp. Bacteroides sp. Bacteroides sp. Acidaminococcusfermentans

clindamycin

i 1 8 1

0.125 0.064 0.25 0.064

27

Bacteroides ruminicola Veillonella parvula Veillonellaparvula I,,actobacillus plantarum Peptostreptococcus micros Bacteroides sp.

clindamycin

1 4

0.032 0,032

penicillin

4 2

0.064 1

penicillin

2 4

Bacteroides corrodens Eikenella corrodens

clindamycin

2

penicillin

0.25

8

44

Streptococcus intermedius Lactobacillus plantarum

penicillin

4 1

0.064 0.5

48

Eikenella corrodens

penicillin

0.064

8

49

Veillonellaparvula

clindamycin

50

Bacteroides sp.

51

Bacteroides sp.

7

21

31 33 38 39

> 16

2 8 0.032

8 > 16 0.25

> 16

0.064

penicillin

1

< 0.008

clindamycin

8

0.064

52

VeiIlonella parvula

clindamycin

2

0,25

55

Bacteroides ruminicola Bacteroides sp.

clindamycin

1 1

~ 0.008 0,125

56

Bacteroides ureolyticus Bacteroides sp.

penicillin

_>16 1

57

Bacteroides sp. Fusobacterium nucleatum

penicillin

1 1

patients in the clindamycin group. The patient in the penicillin group had severe diarrhoea and withdrew from the study on day 2. One patient in the clindamycin group had mild gastrointestinal complaints combined with dizziness, two had mild

0.25 0.25 0,125 0,064

to moderate diarrhoea and three experienced severe diarrhoea. Clostridium difficile and its toxins were detected on day 7 in faeces from one of the patients with severe diarrhoea. However, all patients recovered spontaneously within 12

1134

days from the start of treatment. No other adverse effects were observed. The difference in occurrence of adverse effects between the two treatment regimens was not statistically significant (Fisher's two-tailed exact test).

Discussion

Anaerobic bacteria are by far the most important pathogens in orofacial infections (3). Reports on increasing penicillin resistance among anaerobic bacteria (6, 7, 19, 20) confirm the need for an effective alternative agent to penicillin. The pus samples in the present study yielded 13.6 % penicillin-resistant anaerobic strains, mostly gram-negative rods, only slightly more than the 9.8 % reported by Gilmore et aI. (21). The resistant strains were however recovered from 38 % of the patients in the present study. Thus, the potential risk of orofacial infections with penicillin-resistant Bacteroides strains should not be discounted. It has also been demonstrated that a large number of Bacteroides strains isolated from the oral microflora in healthy volunteers are penicillin-resistant (10). As the penicillin-resistant strains were found as frequently in the penicillin as in the clindamycin group, the presence of penicillin-resistant pathogenic microorganisms does not necessarily result in clinical failure of penicillin therapy. Drainage is as important as antimicrobial treatment, and in these instances the favourable clinical response was probably due to the surgical intervention. However, when immediate drainage is not possible, such as in phlegmonous spread or in patients with dentistophobia, bacterial resistance may influence the clinical response to antimicrobial therapy. Several authors have reported cases of clinical failure of penicillin therapy of orofacial infections due to penicillin-resistant anaerobes (6-8, 22). Most of these patients subsequently responded to treatment with clindamycin or metronidazole. von Konow and Nord (15) conducted a study comparing a nitroimidazole, ornidazole, with penicillin and found ornidazole to be at least as effective as penicillin. Since virtually all anaerobic strains isolated from orofacial infections are highly sensitive to clindamycin in vitro (3), clindamycin was proposed as a potential alternative to penicillin. Gilmore et al. (21) recently undertook a study comparing penicillin to clindamycin in the treatment of odontogenic infec-

Eur. J. Clin. Microbiol. Infect. Dis.

tions and the results revealed a good clinical effect of both penicillin and clindamycin. In the present study the efficacy of treatment was evaluated by documenting the presence of fever, swelling, pain and sleep disturbance, reduction in the erythrocyte sedimentation rate and peripheral white blood cell count, and recurrence of infection or absence of a response to treatment. There tended to be a shorter duration of pain, fever and swelling in the clindamycin group. Thus there was a tendency for clindamycin to be slightly more efficacious than penicillin, with an earlier clinical response. Clindamycin has a significant impact on the indigenous gastrointestinal microflora (12) and occasionally gives rise to severe diarrhoea and even pseudomembranous colitis (11). In the present study a higher rate of adverse gastrointestinal effects was observed in the clindamycin group, and also severe diarrhoea due to Clostridium difficile. The data from the present study support the continued use of penicillin for the treatment of orofacial infections. When penicillin treatment fails due to infection with penicillin-resistant microorganisms or when patients are allergic to penicillin an alternative drug should be used. The findings of the present study are in accordance with earlier results (21), indicating that clindamycin is an effective alternative. However, associated adverse gastrointestinal effects limit the use of antimicrobial agents with a significant impact on the micro flora.

References 1. Finegold SM, Baron E J, Wexler HM: A clinical guide to anaerobic infections. Star Publishing, Belmont, CA, 1992. 2. Bartlett JG, O'Keefe P: The bacteriology of periman-

dibular space infections. Journal of Oral Surgery 1979, 37: 407---409. 3. yon Konow L, Nord CE, Nordenram ~ : Anaerobic bacteria in dcntoalveolar infections. International Journal of Oral Surgery 1982, 10: 313-322. 4. Tabaqchali S: Anaerobic infections in the head and neck region. Scandinavian Journal of Infectious Diseases 1988, Supplement 57: 24-34. 5. Lewis MAO, MacFarlane TW, McGowan DA: A microbiological and clinical review of the acute dentoalveolar abscess. British Journal of Oral and Maxillofacial Surgery 1990, 28: 359-366. 6. Heimdahl A, yon Konow L, Nord CE: Isolation of ~-lactamase-producing Bacteroides strains associated with clinical failures with penicillin treatment of orofacial infections. Archives of Oral Biology 1980, 25: 689-

692.

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7. Heimdahl A, yon Konow L, Nord CE: Clinical significance of penicillin-resistant [3-1actamase-producing Bacteroides species in human orofacial infections. In: Ullman U (ed): Proceedings of the l~-lactam symposium. Springer, Kiel, 1983, p. 49-56. 8. Bahn SL, Ciola B, Segal AG: Penicillin-resistant Bacteroides melaninogenicus infection in the mandible. Journal of Oral Surgery 1981, 39: 221-223. 9. Lewis MAO, MacFadane TW, McGowan DA: Antibiotic susceptibilities of bacteria isolated from acute dentoalveolar abscesses. Journal of AntimicrobiaI Chemotherapy 1989, 23: 69-77. 10. Heimdahi A, yon Konow L, Nord CE: 15-1actamaseproducing Bacteroides species in the oral cavity in the relation to penicillin therapy. Journal of Antimicrobial Chemotherapy 1981, 8: 225-229. 11. Aronsson B, Miillby R, Nord CE: Clostridium difficile and antibiotic associated diarrhoea in Sweden. Scandinavian Journal of Infectious Diseases 1982, Supplement 35: 53-58. 12. Nord CE, Kager L, Heimdahi A: Impact of antimicrobial agents on the gastrointestinal microflora and the risk of infections. American Journal of Medicine 1984, 76: 99-106. 13. Bayliss R, Clarke C, Oakley CM, Sommerviile W, Whiffield AGW, Young SEJ: The microbiology and pathogenesis of infective endocarditis. British Heart Journal 1983, 50: 513-519. 14. Heimdahl A, Mattson T, Dahlliif G, L6nnqvist B, Ringd~n O: The oral cavity as a port of entry for early infections in patients treated with bone marrow transplantation. Oral Surgery, Oral Medicine, Oral Pathology 1989, 68: 711-716.

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15. v0n Konow L, Nord CE: Ornidazale compared to phenoxymethylpeniciUin in the treatment of orofacial infections. Journal of Antimicrobial Chemotherapy 1983, 11: 207-215. 16. Lennette EH, Balows A, Hausler WJ, Shadomy ILl (ed): Manual of clinical microbiology. American Society for Microbiology, Washington, DC, 1985. 17. Ericsson HM, Sherris JC: Antibiotic sensitivity testing. Report of an international collaborative study. Acta Pathologica et Microbiologica Scandinavica 1971, Supplement 217: 64-73. 18. Dornbusch K, Nord CE, Wadstriim 1":. Biochemical characterization and in vitro determination of antibiotic susceptibility of clinical isolates of Bacteroides fragilis. Scandinavian Journal of Infectious Diseases 1974, 6: 253-258. 19. Baker P J, Evans RT, Slots J, Genco RJ: Antibiotic susceptibility of anaerobic bacteria from the human oral cavity. Journal of Dental Research 1985, 64: 12331244. 20. Edson RS, Rosenblatt JE, Lee DT, MeVey EA: Recent experience with antimicrobial susceptibility of anaerobic bacteria. Mayo Clinic Proceedings 1982, 57: 737-741. 21. Gilmore WC, Jacobus NV, Gorbaeh SL, Doku He, Tally FP: A prospective double-blind evaluation of penicillin versus clindamycin in the treatment of odontogenic infections. Journal of Oral and Maxillofacial Surgery 1988, 4: 1065-1070. 22. Whitcher BL, Belrne OR, Smith RA: Beta-lactamaseproducing Bacteroides melaninogenicus and osteomyelitis of the mandible. Journal of Oral Medicine 1983, 38: 17-20.

Clindamycin versus phenoxymethylpenicillin in the treatment of acute orofacial infections.

The efficacy of clindamycin and phenoxymethylpenicillin in the treatment of orofacial infections was compared in a randomised study in 60 patients: 30...
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