Clindamycin versus Phenoxymethylpenicillin in the Treatment of Acute Orofacial Infections

Article Vol. 11. No. 12 1129 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. von Konow 1, Elk, K6ndell 1, C.E. Nord 2,3., A. Heimdahl 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. 3 National 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

1130 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. Clinical Laboratory Investigations. Blood samples were 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. 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 PDM- Antibiotic 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 MIC > 1 mg/l and clindamycin resistance at an MIC > 4 mg/l (18). 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 patients took the tablets in accordance with instructions as revealed by the antibiotic concentrations assayed at all visits. Clinical Outcome. Three patients in the penicillin group discontinued treatment, one because of diarrhoea, one because of the distance to the clinic and one for unknown reasons. Two patients in the clindamycin group discontinued treatment before day 3 because of diarrhoea. The treatment response was satisfactory in all other patients except for one in each group. The patient in the penicillin group had an abscess originating from an infected residual cyst in the upper dental alveolar process, and the patient in the clindamycin group had a periapical abscess originating from an upper canine. On day 7 both patients still demonstrated swelling, fever and presence of purulent material in spite of repeated incisions. Subsequent to incision on day 7 both infections subsided within a few days. Compared to the penicillin group the duration of pain, swelling and fever was less in the clindamycin group and the laboratory findings also tended to be more favourable, but the differences were not statistically significant (Mann-Whitney's U-test). The data are shown in Table 1. Clinical Laboratory Tests. With respect to the erythrocyte sedimentation rate and total white blood cell count there were no differences between the two groups during treatment. None of 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 Duration (days) in clindamycin group Symptom Total Median Range Total Median Range Pain 63 2 0-7 49 2 1-4 Swelling 83 3 0-14 75 2 0-14 Sleep disturbance 29 1 0-4 22 1 0-3 Fever 38 1 0-9 23 0 0-6

Vo1.11,1992 1131 Table 2: Number of aerobic and anaerobic organisms isolated from 59 specimens from patients in the penicillin and elindamycin groups. Organisms Penicillin Clindamycin group group Gram-positive cocci Staphylococcus epidermidis 1 3 Staphylococcus sap roph yticus 3 1 Streptococcus milleri 14 4 Streptococcus mitior 9 9 Streptococcus spp. 3 4 Micrococcus spp. 1 0 Gram-negative cocci 0 1 Gram-positive rods 0 1 Gram-negative rods Haernophilus influenzae 3 0 Haernophilus parainfluenzae 0 2 Other 1 4 Total number of aerobic isolates 35 29 Gram-positive cocci Streptococcus constellatus 6 0 Streptococcus intermedius 8 8 Streptococcus spp. Peptostreptococcus micros 1 12 2 15 Peptostreptococcus spp. 3 3 Gram-negative cocci Veillonella parvula 2 3 Veillonella spp. Other 2 0 1 1 Gram-positive sporeforming rods 0 1 Gram-positive non-sporeforming rods Eubacterium 12 7 Lactobacillus fermentum 1 1 LactobaciUus ptantarum 2 2 Actinomyces odontolyticus 0 3 Other 0 1 Gram-negative rods Bacteroides asaccharolyticus 2 2 Bacteroides corrodens 0 4 Bacteroides ruminicola 8 8 Bacteroides ureolyticus 1 4 Bacteroides spp. 19 28 Eikenella corrodens 3 0 Fusobacterium nucleatum 10 8 Fusobacterium spp. 13 11 Total number of anaerobic isolates 107 t13 the patients showed abnormal levels of haemoglobin, SGOT, SGPT or alkaline phosphatases at any time during the study. Serum concentrations of penicillin and clindamycin indicated good patient compliance. Microbiological Findings. Twenty-three specimens 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

1132 Eur. J. Clin. Microbiol. Infect. Dis. 100 - a~ 80'._= 60' "6 C7 n 40 20 rl A i i i "" i ' i i 1 i " I <0,0080,008 0.016 0.032 0.064 0.125 0.25 0.'5 1,0 2 0 4.0 8.0 16.0 Phenoxymethylpenieillin (mg/i) ' t 8O 60 '~ "6 g 4o 2o <0.0080.008 0,016 0.032 0.064 0.125 0.25 0.5 1.0 2.0 4,0 8.0 '16.0 Clindamycfn (mg/t) Figure 1: Susceptibility of the isolated anaerobic (~-) and aerobic (-*-) bacterial strains to phenoxymethylpenicillin (above) and clindamycin (below). in one specimen. A mean of 4.2 anaerobic strains were isolated from each anaerobic specimen, gram-negative rods being most common. A mean of 4.6 anaerobic strains and 2.2 aerobic strains were isolated from each specimen containing both anaerobes and aerobes. Gram-negative rods were the most common anaerobes while viridans streptococci were the most common aerobes (65 % of all aerobes detected). The two aerobic specimens yielded one aerobic strain each. The microbiological findings are presented in Table 2. Antibiotic Susceptibility. Data on susceptibility of the isolates to penicillin and clindamycin are given in Figure 1. No penicillin- or clindamycin- resistant strains could be isolated from the two patients who did not respond satisfactorily to treatment. A total of 38 (16.6 %) penicillin-resistant (MIC _> 1 mg/1) anaerobic strains were isolated from 23 (38 %) specimens, which were evenly distributed between the two patient groups (Table 3). Among these were 22 anaerobic gram-negative rods, mostly Bacteroides strains. Only five (2%) clindamycin-resistant (MIC > 4 mg/l) anaerobic strains were isolated from four specimens, all from patients in the penicillin group (Table 3). Adverse Effects. Adverse effects were observed in one patient in the penicillin group and in six

Vo1.11,1992 1133 Table 3." Anaerobic organisms resistant to penicillin (MIC ~ 1 mg/1) and/or clindamycin (MIC > 4 mg/l) isolated in the two treatment groups, MIC (rag/l) Patient Organism Antibiotic Penicillin Ciindamyein no. treatment 4 Bacteroides ureolyticus clindamycin > 16 2 6 Eikenella corrodens penicillin 0.064 8 Veillonella parvula 2 0.032 7 Bacteroides ureolyticus clindamycin 2 0.064 8 Fusobacterium nucleatum clindamycin 1 0,064 Bacteroides corrodens 2 0,125 9 Bacteroides rumin&ola penicillin 16 < 0.008 Veillonella parvula 4 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 penicillin 1 0.125 21 Bacteroides sp. clindamycin 1 0.125 24 Eubacterium sp. clindamycin i 0.125 Bacteroides sp. 1 0.064 Bacteroides sp. 8 0.25 Acidaminococcusfermentans 1 0.064 27 Bacteroides ruminicola clindamycin 1 0.032 Veillonella parvula 4 0,032 31 Veillonellaparvula penicillin 4 0.064 I,,actobacillus plantarum 2 1 33 Peptostreptococcus micros penicillin 2 8 Bacteroides sp. 4 > 16 38 Bacteroides corrodens clindamycin 2 0.25 39 Eikenella corrodens penicillin 0.25 8 44 Streptococcus intermedius penicillin 4 0.064 Lactobacillus plantarum 1 0.5 48 Eikenella corrodens penicillin 0.064 8 49 Veillonellaparvula clindamycin > 16 0.064 50 Bacteroides sp. penicillin 1 < 0.008 51 Bacteroides sp. clindamycin 8 0.064 52 VeiIlonella parvula clindamycin 2 0,25 55 Bacteroides ruminicola clindamycin 1 ~ 0.008 Bacteroides sp. 1 0,125 56 Bacteroides ureolyticus penicillin _> 16 0.25 Bacteroides sp. 1 0.25 57 Bacteroides sp. penicillin 1 0,125 Fusobacterium nucleatum 1 0,064 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 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 Eur. J. Clin. Microbiol. Infect. Dis. 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- 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 perimandibular 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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