Bacteriologic Findings Associated with Chronic Bacterial Maxillary Sinusitis in Adults

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1 MAJOR ARTICLE Bacteriologic Findings Associated with Chronic Bacterial Maxillary Sinusitis in Adults S. M. Finegold, 1 M. J. Flynn, 1 F. V. Rose, 2 H. Jousimies-Somer, 1 C. Jakielaszek, 2 M. McTeague, 1 H. M. Wexler, 1 E. Berkowitz, 2 and B. Wynne 2 1 Veterans Affairs Medical Center West Los Angeles and University of California, Los Angeles, School of Medicine; and 2 GlaxoSmithKline Pharmaceuticals, Collegeville, Pennsylvania An open-label, multicenter study was performed to assess bacteriologic findings associated with chronic bacterial maxillary sinusitis in adults. Seventy aerobic (52.2%) and 64 anaerobic (47.8%) pathogens were recovered from clinically evaluable patients at baseline (before therapy). The most commonly isolated anaerobes were Prevotella species (31.1%), anaerobic streptococci (21.9%), and Fusobacterium species (15.6%). The aerobes most frequently recovered included Streptococcus species (21.4%), Haemophilus influenzae (15.7%), Pseudomonas aeruginosa (15.7%), and Staphylococcus aureus and Moraxella catarrhalis (10.0% each). Recurrences of signs or symptoms of bacterial maxillary sinusitis associated with anaerobes were twice as frequent as were those associated with aerobes when counts of anaerobes were 10 3 cfu/ml. A pathogenic role for Granulicatella species in cases of chronic sinusitis was documented for the first time. Chronic sinusitis is one of the most common bacterial infections among adults [1]. Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis have been the predominant aerobic pathogens recovered from patients with acute maxillary sinusitis. When sinusitis becomes chronic, however, these organisms are replaced by a wider variety of both aerobes and anaerobes, and anaerobes play a significant role [2 4]. Special techniques are required for specimen collection and transport and for cultivation of anaerobes [5 7]. Accordingly, reliable data on anaerobic pathogens associated with nonacute sinusitis in adults are limited. Anaerobic streptococci and Prevotella and Fusobacterium species have been identified as predomi- nant anaerobes isolated in previous studies of sinusitis [3, 7 10], but the small sample sizes in these studies and the differences in the collection, transport, and cultivation techniques used have limited the reliability of these data. Detailed bacteriologic data would permit targeted empiric therapy. For example, if Pseudomonas aeruginosa or Staphylococcus aureus were found in the initial specimen, specific coverage would likely be important. Therapy should be adequate to cover b-lactamase producing anaerobes. In the present study, we also assessed the efficacy of amoxicillin/clavulanate for the treatment of chronic bacterial maxillary sinusitis in adults. However, only the findings of bacteriologic studies are reported here. Received 19 November 2001; revised 1 April 2002; electronically published 24 July Financial support: grant from SmithKline Beecham Pharmaceuticals (Collegeville, PA) and VA Merit Review research funds. Reprints or correspondence: Dr. Sydney M. Finegold, Infectious Diseases Section (111 F), VA Medical Center West Los Angeles, Wilshire Blvd., Los Angeles, CA (sidfinegol@aol.com). Clinical Infectious Diseases 2002; 35: by the Infectious Diseases Society of America. All rights reserved /2002/ $15.00 PATIENTS, MATERIALS, AND METHODS Patients. Patient enrollment criteria included age 18 years and a clinical diagnosis of either chronic sinusitis (defined by the presence of symptoms for 6 weeks) or acute exacerbation of chronic sinusitis. Unfortunately, although many patients had their condition classified as chronic sinusitis, the condition of others was simply called sinusitis, and still other patients had 428 CID 2002:35 (15 August) Finegold et al.

2 conditions that were not classified at all by the participating centers. Patients also were required to have abnormal findings (opacification, air-fluid level, or mucosal thickening of 5.0 mm in the affected sinus) on a coronal CT scan and to meet (a) at least 2 major criteria (postnasal discharge, rhinorrhea, facial pain, facial congestion and/or fullness, nasal obstruction and/or blockage, or nasal cavity purulence), or (b) 1 major criterion and 2 minor criteria (tooth pain, earache, headache, sore throat, cough, halitosis, increased wheezing, an oral temperature of 37.8 C, or fatigue). This multicenter study was approved by the institutional review board at each of the participating centers (for a list of investigators and participating centers, please see the Investigators at Participating Centers section that follows the text). Written and verbal informed consent was provided by patients. Bacteriologic investigation. Specimens were obtained by antral puncture of the canine fossa or the lateral nasal cavity wall. Specimens were aspirated by use of a syringe, with instillation of nonbacteriostatic saline done if necessary. Sinus aspirates were injected into anaerobic transport vials (Anaerobe Systems) and were shipped by overnight courier to the Wadsworth Anaerobic Bacteriology Research Laboratory (Los Angeles). Quantitative culture and identification of organisms were done as described elsewhere [11, 12]. Susceptibility testing of isolates with amoxicillin, amoxicillin/ clavulanate, ampicillin, cefuroxime, ciprofloxacin, clarithromycin, and penicillin was done by use of the serial 2-fold agardilution procedure of the National Committee for Clinical Laboratory Standards (NCCLS) [13, 14]. Interpretation. icity was determined using the following criteria: established pathogenicity of the organism, including production of toxins and/or other virulence factors, and dominance of the organism in the infecting flora ( 10 3 cfu/ml). Possible presence of the organism in the normal flora, according to the route of sinus puncture, was also considered. Response to amoxicillin/clavulanate was judged at the end of therapy and at a follow-up visit 3 4 weeks after treatment. Bacteriological eradication was presumed if clinical success was noted and if posttreatment antral puncture was not indicated. RESULTS Bacteriologic findings. A total of 150 (78.9%) of 190 patients completed the study. Bacterial isolates were recovered from 114 (76%) of 150 patients; of 176 organisms isolated, 134 (from 82 patients) were considered pathogens. The average number of organisms isolated per patient was 2.1. Specimens were collected from the canine fossa of 44 patients (53.7%), from the nasal cavity of 37 patients (45.1%), and by an unknown puncture route in 1 patient (1.2%). Of the 134 pathogens, 70 were aerobic and/or facultative and 64 were anaerobes. Most infections were mixed ( n p 39), and infections due to aerobic pathogens only ( n p 36) were more prevalent than infections due to anaerobic pathogens only ( n p 7). Twenty-nine anaerobic species that belonged to 15 genera and 20 aerobic species that belonged to 14 genera were found. Only 1 pathogen was isolated from each of 34 patients (41.5% of 82 patients); 31 of these pathogens were aerobes and 3 were anaerobes (table 1). M. catarrhalis was the most prevalent ( n p 7). The most prevalent anaerobic pathogens (table 2) were Prevotella species ( n p 20), anaerobic streptococci (originally in the genus Peptostreptococcus; n p 14), and Fusobacterium spe- cies ( n p 10). The most prevalent aerobes (table 3) were Strep- tococcus species ( n p 15), Haemophilus species ( n p 11), P. aeruginosa ( n p 11), S. aureus ( n p 7), and M. catarrhalis ( n p 7). Forty of 64 anaerobes were isolated via the canine fossa (table 2), whereas distribution of aerobes was comparable regardless of route of puncture (table 3). Organisms were presumed to be eradicated if a patient showed clinical improvement or was Table 1. Single pathogens isolated from antral sinus puncture specimens obtained from patients with chronic bacterial maxillary sinusitis at baseline. No. isolated Anaerobic Actinomyces gerensceriae 1 Actinomyces viscosus 1 Prevotella melaninogenica 1 Total 3 Aerobic Granulicatella adiacens a 1 Granulicatella elegans a 2 Haemophilus influenzae 3 Moraxella catarrhalis 7 Pseudomonas aeruginosa b 3 Staphylococcus aureus 4 Stenotrophomonas maltophilia 2 Streptococcus pneumoniae 2 Other c 7 Total 31 a Although the pathogenicity of this organism in patients with chronic bacterial maxillary sinusitis has not been established, the organism was isolated as a single pathogen with a count 5 of 10 cfu/ml. b One patient had 3 isolates of P. aeruginosa only, and 2 other patients had 2 different P. aeruginosa isolates only. c Includes 1 each of Enterobacter agglomerans, Escherichia coli, Haemophilus parainfluenzae, Morganella morganii, Pasteurella multocida (no known animal contact), Proteus mirabilis, and group A Streptococcus. Bacteriologic Findings for Sinusitis CID 2002:35 (15 August) 429

3 Table 2. Distribution of 64 anaerobic pathogens recovered from patients with chronic bacterial maxillary sinusitis at baseline, by route of sinus puncture. No. of isolates recovered, by route of sinus puncture Canine fossa Nasal cavity Total no. (%) of isolates Prevotella species (31.3) P. melaninogenica a (7.8) P. intermedia/nigrescens (6.3) P. oris (6.3) P. buccae (3.1) P. oralis (1.6) P. heparinolytica (1.6) P. loescheii (1.6) P. tannerae (1.6) Other (1.6) Anaerobic streptococcal species (21.9) Micromonas micros b (14.1) Finegoldia magna b (3.1) Peptostreptococcus anaerobius (3.1) Anaerococcus prevotii b (1.6) Fusobacterium species (15.6) F. nucleatum (14.1) F. necrophorum (1.6) Actinomyces species (6.3) A. viscosus (3.1) A. gerensceriae (1.6) A. odontolyticus (1.6) Capnocytophaga species (4.7) C. sputigena (1.6) Other (3.1) Dialister pneumosintes (4.7) Eubacterium species (4.7) E. lentum (1.6) E. nodatum (1.6) Other (1.6) Gemella species (4.7) G. morbillorum (3.1) Other (1.6) Bifidobacterium dentium (1.6) Clostridium species (1.6) Eikenella corrodens (1.6) Porphyromonas gingivalis (1.6) Total, no. (%) 40 (62.5) 24 (37.5) 64 (100.0) c a Includes Prevotella melaninogenica/denticola ( ). n p 1 b Formerly called Peptostreptococcus species. c Actual percentage was rounded down (from 100.3%).

4 Table 3. Distribution of 70 aerobic or facultative pathogens recovered from patients with bacterial maxillary sinusitis at baseline, by route of sinus puncture. No. of isolates recovered, by route of sinus puncture Canine fossa Nasal cavity Total no. (%) of isolates Pseudomonas aeruginosa (15.7) Haemophilus influenzae (15.7) Moraxella catarrhalis (10.0) Staphylococcus aureus (10.0) Haemophilus parainfluenzae (5.7) Streptococcus species (21.4) S. intermedius a (7.1) S. constellatus a (5.7) S. pneumoniae (5.7) Group A (2.9) Enterobacter species (4.3) E. agglomerans (2.9) E. aerogenes (1.4) Granulicatella species (4.3) G. elegans (2.9) G. adiacens (1.4) Stenotrophomonas maltophilia (4.3) Citrobacter freundii (1.4) Escherichia coli (1.4) Klebsiella ozaenae (1.4) Morganella morganii (1.4) Pasteurella multocida (1.4) Proteus mirabilis (1.4) Total, no. (%) 34 (48.6) 36 (51.4) 70 (100.0) b a These organisms are classified as aerobes, but they grow better if specimens are transported and cultured anaerobically. b Actual percentage was rounded up (from 98.8%). cured; 124 pathogens were presumed to be eradicated by the end of therapy, and 110 were still presumed to be eradicated at follow-up. Of the 24 pathogens presumed not to be eradicated at follow-up, 6 were associated with treatment failure at the end of therapy and 9 were associated with recurrence of signs or symptoms of bacterial maxillary sinusitis at follow-up. Aerobes ( n p 6) were more commonly associated with treat- ment failure at the end of therapy, whereas anaerobes ( n p 9) were more often associated with recurrence of signs or symptoms of bacterial maxillary sinusitis at follow-up (table 4). P. aeruginosa ( n p 3) and S. aureus ( n p 2) were the principal pathogens associated with clinical failure at the end of therapy. In contrast, Prevotella species ( n p 3) and H. influenzae ( n p 2) were associated with recurrence at follow-up. In addition to the definite pathogens isolated in this study, 42 other organisms were considered not significant (on the basis of low counts of colony-forming units and the probability that they were part of the normal flora). Granulicatella adiacens, which was not previously considered pathogenic in association with bacterial maxillary sinusitis, was found to be the only isolate (count, 10 5 cfu/ml) recovered from 1 patient who had clinical failure at the end of therapy. G. adiacens ( n p 1) and Granulicatella elegans ( n p 2) were also classified as pathogens in 3 other patients because they were present as single isolates with counts of 10 5 cfu/ml. Antimicrobial susceptibility of bacterial isolates. Susceptibility testing of isolates with amoxicillin/clavulanate was performed on 94 of 134 pathogens (52 aerobes and 42 anaerobes; 70.1%) from 65 patients. Forty-one anaerobes and 38 aerobes had an MIC of 1 mg/ml. A single anaerobe (Prevotella intermedia/nigrescens) had an MIC of 8 mg/ml, and 5 different aerobes (P. aeruginosa [9 strains]; Stenotrophomonas maltophilia [2 strains]; and Enterobacter aerogenes, H. influenzae, and Morganella morganii [1 strain each]) had MICs of 32 mg/ml. There were no NCCLS-determined amoxicillin/clavulanate breakpoints for P. aeruginosa, the aerobic pathogen most associated with an MIC of 32 mg/ml in the present study, or for S. maltophilia, another aerobic pathogen associated with an MIC of 32 mg/ml in the present study. Clearly, however, these organisms must be considered resistant. Correlation was poor between MICs of amoxicillin/clavulanate and clinical failure at the end of therapy; 1 of 4 patients had resistant isolates, 2 of 4 had susceptible isolates, and isolates recovered from the remaining patient were not tested. Similarly, of the 8 patients with recurrence of signs or symptoms of chronic bacterial maxillary sinusitis at follow-up, 1 had resistant organisms, 1 had an organism with intermediate resistance, and 6 had susceptible organisms only. Thirty-six patients received antibiotics before study enrollment. This did not correlate with high MICs of amoxicillin/ clavulanate. Penicillin G and ampicillin showed poor activity against staphylococci; one-half to two-thirds of such isolates were resistant to these agents. Prevotella species also showed 50% resistance to these drugs. Thirty-eight of 91 streptococcal isolates, including 2 of 6 S. pneumoniae isolates, were resistant to clarithromycin, and 10 of 15 Haemophilus strains showed intermediate resistance to this agent. A total of 28 of 30 staphylococcal isolates and all 16 Haemophilus isolates evaluated were susceptible to ciprofloxacin. One of 6 S. pneumoniae isolates was resistant to cefuroxime, and 1 of 6 such isolates had intermediate resistance to the agent. DISCUSSION The present study was unique in that it provided quantitation of bacteriologic data, analysis of likely pathogenicity of organ- Bacteriologic Findings for Sinusitis CID 2002:35 (15 August) 431

5 Table 4. s associated with clinical failure at the end of therapy (in 4 patients) or recurrence of signs or symptoms of chronic bacterial maxillary sinusitis (in 8 patients). No. of pathogens associated with Clinical failure at end of therapy (n p 10) Recurrence at follow-up (n p 14) Total no. of pathogens (n p 24) Aerobic Granulicatella adiacens Haemophilus influenzae Moraxella catarrhalis Pseudomonas aeruginosa Staphylococcus aureus Stenotrophomonas maltophilia Anaerobic Bifidobacterium dentium Dialister pneumosintes Fusobacterium nucleatum Gemella morbillorum Micromonas micros Prevotella intermedia/nigrescens Prevotella melaninogenica/denticola Streptococcus constellatus a a This organism is classified as an aerobe, but it grows better if specimens are transported and cultured anaerobically. isms, detailed identification (with up-to-date terminology) of anaerobic and aerobic and/or facultative organisms involved in chronic bacterial maxillary sinusitis, and correlation of bacteriologic findings with clinical failure. Two different routes of antral sinus puncture were compared. Although the association of anaerobes with chronic sinusitis has been reported for many years, the role of such pathogens has not been well understood as a result, in part, of the polymicrobial nature of chronic sinusitis. Previous studies that have evaluated sinus puncture aspirates obtained from patients with chronic sinusitis have yielded mixed findings varying from an absence of anaerobes to anaerobes constituting 56% of all pathogens isolated [3, 4, 7 10]. In studies that used good anaerobic techniques, anaerobes accounted for 25% 56% of isolates [2, 3, 8, 9]. Anaerobes accounted for 48% of the pathogens isolated in the present study. Prevotella species, anaerobic streptococci, and Fusobacterium species accounted for 75% of anaerobic pathogens isolated in the present study, a finding consistent with results of other studies [2 4, 7 10]. Goldstein et al. [15] reported selected antimicrobial susceptibilities of a large number of aerobic ( n p 207) and anaerobic ( n p 162) pathogens iso- lated from antral sinus puncture specimens (type not stated) during They noted a diversity of aerobic and anaerobic bacteria, a finding similar to that of our study. There is no information as to whether the cases of sinusitis in their study were acute or not, and no other clinical data were presented. The distribution of aerobic and/or facultative organisms in the present study was consistent with that seen in other studies of chronic sinusitis. Streptococcus species (21.4%), H. influenzae (15.7%), and M. catarrhalis (10.0%) were among the most frequently isolated aerobic and/or facultative pathogens. Furthermore, consistent with findings of other published studies [3, 4, 7 10], a wide variety of other aerobes and/or facultative pathogens were also recovered (of all such pathogens, 15.7% were P. aeruginosa, 10.0% were S. aureus, and 7.1% were Streptococcus intermedius). The present study indicates that G. adiacens and G. elegans play a significant pathogenic role in chronic bacterial maxillary sinusitis and may account for treatment failure. INVESTIGATORS AT PARTICIPATING CENTERS The investigators (participating centers and/or locations) were Jack Anon (Erie, PA), Stuart Bentkover (Fallon Clinic; Worcester MA), Don Brandon (California Research Foundation; San Diego), Itzhak Brook (Washington, DC), Herbert Daniels 432 CID 2002:35 (15 August) Finegold et al.

6 (Heart of America Research Institute; Mission, KS), B. J. Ferguson (The Eye and Ear Institute; Pittsburgh, PA), Michael Friedman (Chicago), Trevor Ian Goldberg (Charlotte Eye, Ear, Nose, and Throat Associates; Charlotte, NC), Jeffery Hausfeld (Bethesda, MD), Neil Kassman (Statesville Medical Group; Statesville, NC), James McCarty (Hilltop Research; Fresno, CA), Thomas Newbill (Richmond, VA), Michael Poole (University of Texas Medical School at Houston), Donald Pulver (AAIR Research Center; Rochester, NY), Richard Robins (Newport News, VA), Albert Roper (Norfolk, VA), Joram Seggev (Las Vegas, NV), Alan Shikani (The Good Samaritan Hospital; Baltimore, MD), James Stankiewicz (Loyola University Medical Center; Maywood, IL), Richard E. Sterling (Carolina Research; Orangeburg, SC), Brantley Sydnor (Roanoke Ear, Nose, and Throat Clinic; Roanoke, VA), and Kevin J. Wingert (Sierra Medical Research; Fresno, CA). Acknowledgment We would like to thank the investigators at the participating centers who participated in and made specimens from their patients available for this study. References 1. Benson V, Marano MA. Current estimates from the National Health Interview Survey, Vital Health Stat 1998; series 10(199): Nord CE. The role of anaerobic bacteria in recurrent episodes of sinusitis and tonsillitis. Clin Infect Dis 1995; 20: Brook I, Frazier EH, Foote PA. Microbiology of chronic maxillary sinusitis: comparison between specimens obtained by sinus endoscopy and by surgical drainage. J Med Microbiol 1997; 46: Brook I, Frazier EH, Foote PA. Microbiology of the transition from acute to chronic maxillary sinusitis. J Med Microbiol 1996; 45: Finegold SM. Anaerobic bacteria: general concepts. In: Mandell GL, Bennett JE, Dolin R, eds. Principles and practices of infectious diseases. 5th ed, vol 2. Philadelphia: Churchill Livingstone, 2000: Finegold SM. Overview of clinically important anaerobes. Clin Infect Dis 1995; 20(Suppl 2):S Wald ER. Microbiology of acute and chronic sinusitis in children and adults. Am J Med Sci 1998; 316: van Cauwenberge PB, Ingels KJAO, Bachert C, Wang DY. Microbiology of chronic sinusitis. Acta Otorhinolaryngol Belg 1997; 51: Brook I. Bacteriology of chronic maxillary sinusitis in adults. Ann Otol Rhinol Laryngol 1989; 98: Biel MA, Brown CA, Levinson RM, et al. Evaluation of the microbiology of chronic maxillary sinusitis. Ann Otol Rhinol Laryngol 1998; 107: Baron EJ, Pfaller MA, Tenover FC, Yolken RH, eds. Manual of clinical microbiology. 7th ed. Washington, DC: ASM Press, Summanen P, Baron EJ, Citron DM, et al. Wadsworth anaerobic bacteriology manual. 5th ed. Belmont, CA: Star Publishing, National Committee for Clinical Laboratory Standards (NCCLS). NCCLS performance standards for antimicrobial disk susceptibility tests, approved standard. 6th ed. NCCLS Document M2-A6. Wayne, PA: NCCLS, 1997:vol. 17, no National Committee for Clinical Laboratory Standards (NCCLS). Methods for antimicrobial susceptibility testing of anaerobic bacteria, approved standard. 4th ed. NCCLS Publication M11-A4. Wayne, PA: NCCLS, 1997:vol. 17, no Goldstein EJC, Citron DM, Merriam CV. Comparative in vitro activities of amoxicillin-clavulanate against aerobic and anaerobic bacteria isolated from antral puncture specimens from patients with sinusitis. Antimicrob Agents Chemother 1999; 43: Bacteriologic Findings for Sinusitis CID 2002:35 (15 August) 433