Vol. 110 No.

2 August 2010

ORAL AND MAXILLOFACIAL SURGERY

Editor: James R. Hupp

Antibiotic susceptibility and resistance of the odontogenic microbiological spectrum and its clinical impact on severe deep space head and neck infections
Paul W. Poeschl, MD, DMD,a Ludwig Spusta, DMD,a Guenter Russmueller, MD,a Rudolf Seemann, MD, MS,a Alexander Hirschl, MD, PhD,b Ellen Poeschl, MD, DMD,a Clemens Klug, MD, DMD, PhD,a and Rolf Ewers, MD, DMD, PhD,a Vienna, Austria
MEDICAL UNIVERSITY OF VIENNA

Objective. The purpose of this retrospective study was to identify the major pathogens responsible for deep space head and neck infections and their current resistance to routinely used antibiotics in a university hospital setting. Study design. A total of 206 patients suffering from odontogenic deep space infections were treated at our department by means of surgical intervention and intravenous administration of antibiotics. Results. The predominant bacteria were viridans group streptococci (VGS), staphylococci, Prevotella, Peptostreptococcus, and Bacteroides. In the aerobic spectrum, resistance against clindamycin was found in 18%, against macrolides in 14%, and against penicillin G in 7%. The anaerobes were resistant to clindamycin in 11%, to metronidazole in 6%, and to penicillin G in 8%. Conclusion. The high resistance rate for clindamycin and macrolides was especially striking and may necessitate an adaptation of our antibiotic regime in the future. (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2010;110: 151-156)

Although the incidence of severe head and neck deep space infections requiring hospitalization, extraoral incision, and drainage has decreased, the clinical challenge of their proper treatment, especially in life-threatening cases, remains the same. Due to the routine administration of broad-spectrum antibiotics, severe complications nowadays are rarely seen. Despite the general decrease of cases with severe complications like mediastinitis, thoracic empyema, pericarditis, or septic shock with general multiorgan failure can occur, especially in patients with associated systemic diseases. Further sequelae may be the inevitable hospitalization at an intensive care unit and mortality rates up to 50%.1 Among the coma

monly used antibiotics, penicillins still remain the drugs of rst choice, because of their safe use, minimal side effects, and broad spectrum, especially in combination with beta-lactamase inhibitors. Nevertheless, the occurrence of penicillin resistance and the increasing resistance to other antibiotics, such as clindamycin and macrolides, more and more becomes a challenge in clinical practice. The purpose of the present retrospective study was to identify the major pathogens responsible for head and neck deep space infections and their current resistance status to commonly used antibiotics in a university hospital setting. PATIENTS AND METHODS A total of 206 patients with the diagnosis of an odontogenic head and neck deep space infection were treated at the University Hospital for Craniomaxillofacial and Oral Surgery of Medical University of Vienna between January 2005 and March 2008. Our clinic is the biggest unit for craniomaxillofacial and oral surgery in Austria and covers 151

University Hospital for Craniomaxillofacial and Oral Surgery. Department for Clinical Microbiology. Received for publication Sep 29, 2009; returned for revision Nov 18, 2009; accepted for publication Dec 23, 2009. 1079-2104/$ - see front matter 2010 Mosby, Inc. All rights reserved. doi:10.1016/j.tripleo.2009.12.039
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Fig. 1. Age distribution (years of age) as percentage of all cases.

Fig. 2. Spaces involved as percentages of all cases.

greater Vienna, including the adjacent parts of the rural districts of lower Austria. Almost all patients were referred to our department by dentists or general practitioners, and only 5% came by themselves. Patients data were obtained from chart review, compiled databases, and clinical follow-up. All patients underwent surgical incision from an extraoral approach, including drainage, and received IV antibiotics. The causative tooth was removed whenever possible. All cases where an intraoral incision was sufcient were not included in the study. The routine treatment also consisted of the administration of analgesics and antiinammatory drugs. The evaluated parameters included gender, age, site of space infection, dental origin, duration of hospitalization, type of antibiotic administered, microbiologic spectrum, and antibiograms. Culture and susceptibility testing The swabs (Copan Italia, Brescia, Italy) taken after incision were inoculated into the following media: Columbia-agar 5 % sheep blood, streaked with a single line of S. aureus (incubated in a humied incubator with 5% CO2 at 36 1C up to 5 days), Mc Conkey agar (aerobic incubation, 36 1C, 48 h), Schdler and KVL agar (anaerobic conditions, 36 1C up to 5 days, Chromagar Candida (aerobic incubation, 36 1C up to 7 days). In addition, the swabs were placed into brain heart infusion 0.1% agar (aerobic incubation, 36 1C up to 5 days). All bacteria were identied to species level (bacteria of the normal skin ora only when growing in pure culture and at least moderate amount) using standard methods. Antimicrobial susceptibility testing except for strict anaerobic bacteriawas performed by means of the agar disk diffusion method following the respective Clinical and Laboratory Standards Institute (CLSI) guidelines.2 Anaerobic bacteria were tested by means of the Etest (BioMeriux, Marcy lEtoile, France). The inter-

Table I. Culture results for the aerobic spectrum

Aerobic spectrum Streptococcus viridans (VGS)* Streptococcus anginosus Streptococcus mitis Streptococcus intermedius -Hemolytic streptococci Staphylococcus epidermis Staphylococcus capitis Staphylococcus aureus Staphylococcus hominis Corynebacterium spp. Proteus vulgaris Haemophilus spp. Escherichia coli Enterobakter cloacae Candida albicans MRSA Total No. of strains isolated (% of total aerobic strains) 35 (28%) 6 (5%) 5 (4%) 4 (3%) 23 (18%) 7 (6%) 5 (4%) 7 (6%) 6 (5%) 3 (2%) 4 (3%) 4 (3%) 3 (2%) 4 (3%) 10 (8%) 1 (0.8%) 127

*Viridans group streptococci. Streptococcus constellatus, S. anginosus, and S. mitis were tested separately and are not included in VGS. Number of all strains (aerobes anaerobes) 178.

pretation of the MIC (minimal inhibitory concentration) values followed the respective CLSI guideline.3 RESULTS All 206 patients were successfully treated by surgical and antibiotic therapy. There were 121 (59%) male and 85 (41%) female patients, and the mean age was 36 years (range 5-105 years; Fig. 1). The submandibular space (34.1 %) was the most frequent site of infection (Fig. 2). In 34%, multiple spaces were involved. In 4 patients (1.9%), a second or third surgical intervention was necessary because of disease progression. Three patients (1.5%) had to be hospitalized at our intensive care unit because of multiorgan involvement in the context of septicemia. These cases were considered to be antibiotic failures, because in all 3 patients the administered antibiotic did not cover the bacterial spectrum found in the culturing assay.

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Table II. Culture results for the anaerobic spectrum

Anaerobic spectrum Prevotella spp. Prevotella oralis Prevotella buccae Prevotella bivia Prevotella corporis Fusobacterium necrophorum Porphyromonas gingivalis Eikenella spp. Eikenella corrodens Peptostreptoccus spp. Bacteroides spp. Bacteroides stercoris Total No. of strains isolated (% of total anaerobic strains) 19 (37%) 2 (4%) 2 (4%) 1 (2%) 1 (2%) 3 (6%) 1 (2%) 2 (4%) 3 (6%) 11 (22%) 4 (8%) 2 (4%) 51

strains). The rates for penicillin (7%-8% of tested strains) were lower than for clindamycin, and the aminopenicillins showed very low resistance rates (0-3% of tested strains). Resistant bacteria against erythromycin were found in 14% of the tested strains, whereas only aerobic rods were tested for erythromycin. DISCUSSION Deep space head and neck infections today are still among the most frequent clinical pictures within the maxillofacial area and mostly require an immediate and accurate treatment.4,5 Usually the origin arises from an odontogenic problem,6,7 despite the generally improved availability of professional dental treatment. In the majority of the cases, surgical incision, removal of the causative tooth, and administration of broad-spectrum antibiotics is the treatment of rst choice and sufcient.6,7 Nevertheless, there are sometimes severe cases where the disease proceeds and the patients life is endangered due to complications such as mediastinitis, septic shock, and consecutive multiorgan failure.7 This being said, the need for safe, effective, and well tolerated antibiotic substances is obvious within a clinical setting.6 Since the discovery of the rst antibiotic substance by Sir Alexander Fleming in 1928, the research and development of antibiotics has played a big role within the pharmaceutics industry, and numerous substances of different classes and therapeutic mechanisms have been found.8 The penicillins today are still widely used and are often the antibiotics of rst choice.9 This is mainly due to their effectiveness, low costs, and good compatibility. Because of the appearance of bacterial resistance against the penicillins other substances were developed.10 But concern exists about the potential risk of an increase of bacterial resistance even against modern synthetic antibiotics.11 To clarify this presumption was one aim of the present study. Today we know that in the majority of cases, a mixed anaerobic-aerobic bacterial ora is the causative agent.6,7,9 In the study by Eckert et al.,9 the percentage of mixed infections was 71% compared with 58% in our series. Eckert et al. also pointed out a striking rate of anaerobic monoinfections in their prospective series, identifying anaerobes as the sole pathogen in 12% of cases. The presence of anaerobic monoinfections in our study was lower, accounting only for 5% of all cases. In general, the ratio between aerobes and anaerobes differs in the literature.12,13 Current data show an increasing rate of anaerobic rods.9,12,13 This may be due to an improvement of isolating and culturing techniques.14 Usually anaerobic strains need more time in the culture and are, of course, more sensitive to milieu changes during their transport from the operating room into the

The individually presented prevotellae, eikenellae, and Bacteroides are not included in the corresponding spp. groups. Number of all strains (aerobes anaerobes) 178.

The dental focus was identied in all cases. In 94% of the cases, the causative tooth could be found in the mandible. The mean time of hospitalization was 8 days (range 5-65 days), and the mean duration of IV administration of antibiotics was 5.2 days (range 1-39 days), followed by oral administration. The majority of patients (78%) received a combination of amoxicillin and clavulanic acid, which is the antibiotic of rst choice at our department. In almost all other cases, or if an allergy against penicillin was known or suspected, clindamycin was usually prescribed (18%). The remaining 4% received ciprooxacin, moxioxacin, macrolides, vancomycin, piperacillin/tazobactam, second- or third-generation cephalosporins, or metronidazole. From all 206 patients, a total of 180 specimens of purulence were collected by means of swabbing technique. A total of 178 strains were identied (as presented in Tables I and II) in 144 cases (1.2 isolates/patient); in 36 cases no microorganisms could be detected. Candida species were found in 10 cases. The most frequent bacteria were viridans group streptococci (VGS) and staphylococci among the aerobic strains. Within the anaerobic spectrum, rods of Prevotella and Peptostreptococcus dominated. The detailed results for the cultures are depicted in Tables I and II. Sensitivity testing was performed only for the leading pathogens (144 strains) in 126 cases (out of 144 positive cultures cases) for the following antibiotics: penicillin G, aminopenicillins, aminopenicillins and clavulanic acid, clindamycin, erythromycin, fosfomycin, and metronidazole. The results for sensitivity testing are shown in Tables III and IV. The results indicated high resistance rates of the tested strains for clindamycin (11%-18% of tested

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Table III. Sensitivity testing for the aerobic spectrum (leading pathogens only)
Aerobic spectrum Streptococcus spp. Staphylococcus spp. MRSA Total (n) Total (%) n 73 25 1 99 100% S-test 69 20 1 90 91% Pen G 2 (3%) 3 (14%) 1 6 7% AP 1 (1.5%) 1 (5%) 1 3 3% AP BLI 0 0% Erythro 9 (13%) 3 (14%) 1 13 14% Clind 11 (16%) 4 (19%) 1 16 18% Fosf 1 1 1%

n, Number of strains isolated according to Table I; S-test, sensitivity test, number of strains tested; Pen G, penicillin G resistance; AP, aminopenicillin resistance; BLI, beta-lactamase inhibitor resistance; Erythro, erythromycin resistance; Clind, clindamycin resistance; Fosf, fosfomycin resistance.

Table IV. Sensitivity testing for the anaerobic spectrum (leading pathogens only)
Anaerobic spectrum Prevotella spp. Fusobacterium Bacteroides spp. Peptostreptococcus spp. Total (n) Total (%) n 25 3 6 11 45 100% S-test 21 2 4 9 36 80% Pen G 3 (14%) 3 8% AP 0 0% Clind 2 (10%) 1 (25%) 1 (11%) 4 11% Metro 1 (50%) 1 (11%) 2 6%

n, number of strains isolated according to Table II; Metro, metronidazole resistance; other abbreviations as in Table III.

laboratory.15 Therefore, it can be assumed that many anaerobes do not survive the procedure of swabbing and transport and therefore are not found as causative pathogens in the culture results. The meticulous disinfection of the skin or mucosa before puncturing and aspirating or swabbing as well as a short transport time in suitable media is required for the sufcient identication of anaerobic strains.9,12,13 Generally, in studies where the swabbing technique was used the predominant species were gram-positive aerobes, whereas aspiration of pus specimen led to more anaerobic rods in the culture.12,13 Our data support these ndings in exhibiting an aerobic:anaerobic ratio of 2.5:1, whereas Eckert et al.9 found an opposite ratio of aerobic:anaerobic strains of 1:2. In their study, the aspiration technique was used, wherease our series used the swabbing technique. Another crucial point, as already mentioned, is the duration of culturing. Anaerobes usually need a longer culture time, up to 7-10 days. Of course, this time period is quite long compared to the urgent need of signicant antibiograms to provide for a sufcient and proper treatment.6 Against this background, it is important to have powerful and safe rst-line antibiotics which reliably cover most of the causative bacterial spectrum to avoid initial therapy failure with eventual severe and life-threatening consequences for the patients.6,7 As mentioned earlier, consent exists in the literature about the major pathogens of odontogenic infections, although their percentages of distribution may vary.7 Among the aerobic spectrum, viridans group strepto-

cocci and staphylococci are predominate, and among the anaerobic spectrum, usually gram-negative rods such as Prevotella and Bacteroides or gram-positive strains such as Peptostreptococcus are seen as causative. The results of the present study support these ndings (Tables I and II). Therefore the main goal of any therapeutic antibiotic administration should primarily focus on these specic bacteria.6 It is known that uncritical and frequent application of antibiotics may easily lead to the development of bacterial resistance16 due to the pressure of selection carried out on the bacteria. The clinical impact of this observation is obvious and should be considered by every clinician in everyday life. Flynn et al.17 encountered a penicillin failure rate of 21% in severe odontogenic infections. Eckert et al.9 reported an overall resistance rate of only 7.3%, which seems to be very low. From the literature, it is known that the increase of penicillin resistance is mainly observed within the anaerobic gram-negative spectrum,11 especially among Prevotella, Bacteroides, and Fusobacterium. Resistance rates up to 60% are described and reported.11 Our data show slightly higher penicillin resistance rates for gram-negative anaerobes (8%) compared with gram-positive aerobes (7%). Penicillin resistance occurs mainly because of the synthesis of beta-lactamase by the bacteria.18 Usually beta-lactamase producing strains are found among the gramnegative spectrum. Fusobacterium and Prevotella (pigmented), in particular, are able to split beta-lactamase antibiotics. On the other hand, it is known that almost all beta-lactamases of the clinically relevant bacteria in

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odontogenic infections are neutralised by clavulanic acid, which is a widely used beta-lactamase inhibitor.19 The overall resistance rates of the different bacteria in the present study are quite surprising. Streptococci showed very low resistance rates to penicillins (3%), but exhibited high resistance rates to erythromycin (13%) and clindamycin (16%). Staphylococci demonstrated even worse results. The penicillin resistance rate was 14%, compared with erythromycin 14% and clindamycin 19%. Compared with other studies,11 the situation for clindamycin is especially worrying. Among the anaerobic spectrum we observed overall resistance rates of 8% for penicillins and 11% for clindamycin. The situation for metronidazole seems to be quite favorable, with a rate of 6% of bacterial resistance. Favorably low resistance rates were found for aminopenicillins with 3% for aerobes and none for anaerobes. At our clinic, there are usually only 2 different antibiotics used in 90% of all cases. The rst-line drug is a combination of amoxicillin and clavulanic acid, and the second is clindamycin, which is routinely administered in cases of suspected penicillin allergy or intolerance. We never use penicillin G or penicillin V for our patients. This is mainly due to the indicated resistance rates, which can reach up to 60% within the anaerobic spectrum.11 Therefore, the combination of amoxicillin/clavulanic acid seems to be the safer and more effective medication, because almost no cases of resistance are known9 (Tables III and IV). We did not observe any clinical antibiotic failure for amoxicillin/ clavulanic acid. In contrast, the high resistance rates for clindamycin are alarming and we could observe 3 clinical failures, which necessitated further surgical interventions and a change in the antibiotic regime. Against this background we are currently evaluating the application of moxioxacin in penicillin-allergic patients, because of its known broad-spectrum activity similar to amoxicillin and clavulanic acid.20-22 Erythromycin and metronidazole are rarely used in our department and are not drugs of rst choice. In the daily routine there is a need for safe, well tolerated, and efcient antibiotics to reduce the risk of treatment failures, which can lead to life-threatening sequelae for the patients. The routine use of the broad-spectrum combination amoxicillin/clavulanic acid proved to be of value, and we could not observe any noteworthy side effects, such as impaired liver function or anaphylactic shock. Because of the broader activity and easier handling properties (administration only once daily), the use of moxioxacin instead of clindamycin in penicillin-allergic patients seems worth considering, not least because of the high resistance rates for clindamycin in our series

and other studies.20-22 Further prospective studies are necessary to compare these substances in a clinical setting. Nevertheless the use of broad-spectrum antibiotics has to be safely evaluated, because of the potential development and promotion of resistant strains. The reasons for their application have to be balanced on a patient-to-patient basis.
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et al. Susceptibility of oral obligate anaerobes to telithromycin, moxioxacin and a number of commonly used antibacterials. Oral Microbiol Immunol 2007;22:298-303. Reprint requests: Paul W. Poeschl University Hospital for Craniomaxillofacial and Oral Surgery Medical University of Vienna Waehringer Guertel 18-20 A-1090 Vienna Austria wolfgang.poeschl@meduniwien.ac.at

19. Bush K. Classication of beta-lactamases: groups 2c, 2d, 2e, 3, and 4. Antimicrob Agents Chemother 1989;33:271-276. 20. Diz Dios P, Toms Carmona I, Limeres Posse J, Medina Henrquez J, Fernndez Feijoo J, Alvarez Fernndez M. Comparative efcacies of amoxicillin, clindamycin, and moxioxacin in prevention of bacteremia following dental extractions. Antimicrob Agents Chemother 2006;50:2996-3002. 21. Sobottka I, Cachovan G, Strenburg E, Ahlers MO, Laufs R, Platzer U. In vitro activity of moxioxacin against bacteria isolated from odontogenic infections. Antimicrob Agents Chemother 2002;46:4019-4021. 22. Toms I, Toms M, Alvarez M, Velasco D, Potel C, Limeres J,