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REVIEW ARTICLE

The Role of Anaerobic Bacteria in Recurrent Episodes of and Tonsillitis

Carl Erik Nord From the Department of Microbiology, Karolinska Institutet, Huddinge University Hospital, Huddinge, Sweden

Chronic and recurrent upper represent a significant clinical chal-

lenge. The causative organisms tend to be heterogeneous, involving both aerobes and gram-posi- Downloaded from https://academic.oup.com/cid/article/20/6/1512/477393 by guest on 27 September 2021 tive and gram-negative anaerobes. There is evidence that these mixed groups of bacteria interact synergistically, enhancing and prolonging the overall virulence of . The role of anaerobic bacteria, in particular their proposed ability to protect susceptible organisms by the production of ft-lactamases, has been the subject of intense speculation. The evidence of a significant role for anaerobic bacteria in recurrent episodes of tonsillitis and sinusitis is reviewed and the most appropriate antimicrobial strategies and possible future developments in diagnosis and therapy are discussed.

The Lingering Threat of Sinusitis and Tonsillitis sinusitis and tonsillitis and clarifies appropriate future direc- tions for clinical management. There are a number of reasons why upper respiratory tract infections such as sinusitis and tonsillitis remain a serious problem. First, while chronic and recurrent up- The Shift in Microbial Flora Associated with Chronic per respiratory tract infections are generally not life-threaten- Tonsillitis and Sinusitis ing, they are common, are refractory to treatment, and ac- Normal Flora of the Upper Respiratory Tract count for a large proportion of physician visits and health care expenditures. Second, it has been suggested that chronic . The tonsils are masses of lymphatic tissue that upper respiratory tract infections are associated with a shift play a role in protecting the body against infection. The ratio in microflora, which encourages the emergence of resistant of anaerobes to aerobes in the healthy human oropharynx is organisms, particularly in conjunction with misuse of antimi- 10:1 [3, 4]. The normal core harbors polymicrobial crobials. Third, chronic sinusitis and tonsillitis may poten- flora, including anaerobes such as Prevotella species and Por- tially act as sources for more serious secondary infections [ 1]. phyromonas species (formerly classified in the Bacteroides For example, chronic sinusitis is generally a mild disease, but group [5, 6]) and aerobes such as streptococci and staphylo- it can lead to infectious complications involving the CNS cocci [7]. Prevotella interinedia (formerly Bacteroides inter- such as brain and meningitis. In cases of tonsillitis, medius) has been found in high concentrations on the tonsil failure to eradicate streptococci can still occasionally lead to surface in healthy individuals, and Porphyromonas gingivalis the development of rheumatic and glomerulonephritis. (formerly Bacteroides gingivalis) has also been recovered [8, The association of sinusitis and tonsillitis with secondary in- 9]. The microflora in the entire oral cavity undergoes charac- fections became less significant following the introduction of teristic changes during the maturation of an individual from modern antimicrobials, resulting in more-effective elimina- infancy to adulthood [10]. tion of primary infection. However, with the increase in lev- Sinuses. The sinuses are air-filled cavities located within els of bacterial resistance [2], treatment failures may return the frontal, ethmoidal, maxillary, and paranasal bones of the to their former rate unless antimicrobial strategies are effec- skull. They open into the nasal cavity and are lined with tively adapted in response to changing resistance patterns. mucous membrane continuous with the nasal mucosa. Their This review outlines our current understanding of the an- function is to reduce the weight of the skull. Some investiga- aerobic microorganisms involved in recurrent episodes of tors have attempted to define the bacteriology of the healthy sinus [1 1]. For this study maximum effort was made to avoid contamination, and all 12 aspirates from the maxillary si- nuses of volunteers showed no bacterial growth; however, Received 29 August 1994: revised 7 December 1994. other studies have yielded conflicting results. In a study by Reprints or correspondence: Dr. Carl Erik Nord, Department of Microbi- Brook [12], bacteria were isolated from 12 of 12 healthy si- ology F88, Huddinge University Hospital, S-I4 I 86, Huddinge, Sweden. nuses examined (it should be noted that the sinuses aspirated Clinical Infectious Diseases 1995;20:1512-24 (1) 1995 by The University of Chicago. All rights reserved. were those of patients with facial anomalies requiring correc- 1058-4838/95/2006-0008802.00 tive surgery); the bacteria that were recovered included both CID 1995;20 (June) Recurrent Sinusitis and Tonsillitis 1513

aerobes (Staphylococcus aureus, pneumoniae, and interfere with breathing and swallowing. Since and Haemophilus parainfluenzae) and anaerobes (Bacter- the mucous membranes of the pharynx, eustachian tubes, oides species, Prevotella species, anaerobic cocci, and Fuso- and middle ear are continuous, an infection may travel from bacterium species) [12]. the into the middle ear. The specific location of the different sinuses affects their A major difference between the microbial flora in episodes microenvironmental conditions, which will determine the of and chronic tonsillitis is the increased numbers of nature of their normal flora. For example, the atmosphere of anaerobes isolated from patients with the chronic disease the ethmoidal sinus is relatively aerobic as a result of in- (i.e., in terms of cfu per gram [7]), and this variation is re- creased exposure to inspired oxygen [13]. lated to microenvironmental and structural changes in the chronically infected tissue. Tables 1 and 2 indicate the per- centages of aerobes vs. anaerobes isolated from children and Downloaded from https://academic.oup.com/cid/article/20/6/1512/477393 by guest on 27 September 2021 Microbial Flora Associated with Acute Sinusitis and Tonsillitis adults with chronic tonsillitis. The most frequently isolated Tonsillitis. Tonsils are common sites of infection, and anaerobes were Bacteroides species, Fusobacterium species, of the tonsils is termed tonsillitis. Acute tonsil- Prevotella species, and anaerobic cocci. litis is usually a self-limited disease. It is common, particu- The proportion of anaerobes isolated from patients with larly in children and young adults, and constitutes 60% of chronic tonsillitis is highly variable (33%-88% of organisms upper respiratory tract infections. The majority of cases of detected in different studies were anaerobes). It is important tonsillitis are of viral origin. Of those cases due to bacteria, to make a distinction between variations that represent tech- most are caused by group A 13-hemolytic streptococci; how- nical artifacts and those that are clinically significant. Dis- ever, other bacteria have also been implicated including S. crepancies between sampling techniques and culture meth- aureus, S. pneumoniae, , and anaer- ods may give rise to artifactual variations in the obes [1, 14]. It has also been suggested in some reports that aerobe-to-anaerobe ratio. A number of investigators, includ- Mycoplasma and Chlantydia are pathogens of the upper respi- ing Bieluch et al. [27] and Gaffney et al. [29], used direct ratory tract. For instance, Chlamydia trachomatis and Myco- plating rather than the fluid enrichment technique favored plasma pneumoniae have been identified in adults with phar- by Brook et al. [32]. Furthermore, the former two groups yngitis, both by positive culture and by serological tests [15, incubated their plates for only 48 hours in an attempt to 16]. However, the reports of isolation of these organisms identify those anaerobes present in clinically significant num- vary widely, which is probably a result of the technical diffi- bers; in contrast, Brook et al. incubated their plates for 96 culties in their identification. It has been found that C. tra- hours. chomatis may be difficult to recover from the oropharynx: Technical variations also arise when the tonsils are excised passage is required for isolation in over one-half of the cul- prior to sampling. In some studies a heated scalpel was used tures [15]. False-positive reactions can occur in serological to cauterize the tonsil surface prior to incision, thereby tests [16]. Thus, further studies on the potential role of Chia- avoiding surface contamination [29]; other investigators inydia and Mycoplasma in upper respiratory tract infections, have deemed this surface-sterilization procedure unneces- including chronic tonsillitis, are required. sary [19]. In addition, the sterilization method has varied Sinusitis. Sinusitis accounts for 10% of upper respiratory within the same study [29]: some of the tonsils were soaked tract infections and occurs when drainage of mucous secre- in alcohol-iodine solution for 5 minutes and rinsed in sterile tions from a sinus is blocked by swollen membranes, usually saline, while others were not. The method of homogeniza- resulting from a nasal infection (generally viral) or allergic tion of tonsil tissue also varied: in one study the tissue was reaction [ I]. Accumulation of fluid in the sinuses then causes ground with a pestle and mortar [27], and in another study it increased pressure and results in a painful sinus headache. was chopped with scissors [19], which may affect the level of The pathogens most frequently isolated from patients with aeration. Such technical variations may influence the types acute bacterial sinusitis are S. pneumoniae and H. influenzae, and numbers of anaerobes recovered. but a wide range of other organisms have also been isolated, Despite these technical differences, there are likely to be including S. aureus, Moraxella catarrhalis, Streptococcus pyo- genuine differences in the microbial flora that are associated genes, and anaerobes [1, 17]. with factors such as region (surface or core) of the tonsil investigated and prior use by the individual. A number of studies [29, 31-33] have indicated a wide varia- Anaerobes Increasingly Associated in Cases of Chronic tion between the microbiology of the surface of the tonsil Tonsillitis and Sinusitis and that of the core: more anaerobes are isolated from the Chronic tonsillitis. Chronic tonsillitis usually manifests core than from the surface, which reflects the different oxy- as a recurrent that is sometimes accompanied by gen tensions of the two microenvironments. Therefore, if foul breath. In children, the chronically infected tonsils may is not performed, a complete microbial evalua- become so swollen that they block the passageways of the tion may only be achieved by fine-needle aspiration of the 1514 Nord CID 1995;20 (June)

Table 1. Summary of evidence of the role of anaerobes from studies of recurrent tonsillitis in children.

Percentage of Percentage patients from whom of organiSms Anaerobic species No. of organisms were that were (in approximate order [References] patients Condition isolated anaerobes of prevalence)

[18] 50 Excised tonsils* 100t 535 Prevotella, Bacteroides. Fusobacterium, Peptococcus. Veillonella, Peptostreptococcus, Eubacterium, Propionibacterium, Actinomyces, Lactobacillus Downloaded from https://academic.oup.com/cid/article/20/6/1512/477393 by guest on 27 September 2021 [19] 41 Excised tonsils* 1001 781 Prevotella, Bacteroides, Fusobacterium, Peptostreptococcus, Peptococcus, Leptotrichia, Eubacterium, Bifidobacterium [19] 37 Recurrent tonsillitis 95 88 Prevotella, Bacteroides, Fusobacterium, Eubacterium, Veillonella, Peptostreptococcus [20] 50 Excised tonsils* IOW 56* Prevotella, Bacteroides, Fusobacterium, anaerobic cocci, Veillonella [21] 20 Excised tonsils* 1001 NS Bacteroides. Prevotella, Fusobacterium, Veillonella, anaerobic cocci [22] 40 Excised tonsils* 100t 61 Prevotella. Bacteroides, Fusobacterium, Peptostreptococcus, Veillonella. Lactobacillus, Actinomyces, Porphyromonas, Bifidobacterium, Eubacterium, Propionibacterium [23] 43 Recurrent tonsillitis 100 43 Prevotella, Porphyromonas, Bacteroides [7] 4 Excised tonsils* 1001 631 Prevotella, Bacteroides, Peptostreptococcus, Veillonella. Fusobacterium, Lactobacillus, Bifidobacterium, Porphyromonas

NOTE. NS = not stated. * History of recurrent tonsillitis. Includes organisms isolated from core of tonsil. * History of recurrent tonsillitis; at time of tonsillectomy, tonsils not clinically inflamed. tonsil core [29], which in practice may not be feasible with- less susceptible to the presence of oxygen in the tissues than out the use of sedatives and/or local anesthetics. are anaerobes. This initial colonization by aerobes leads to a Brook and Leyva [34] determined that there was also no reduced oxygen tension, which favors the growth of anaero- correlation between the microbes cultured from each of the bic organisms [35]. Anaerobic conditions are enhanced by two tonsils of the same individual. Most investigators swab structural damage to the tonsils, such as scarring, that results only one tonsil in order to minimize discomfort for the pa- from prolonged bacterial infection [26]; this environment tient, but this practice may result in the absence of important encourages the proliferation of endogenous anaerobic flora microbiological data. Another important point is that tonsil- [19]. The major microbiological shifts that occur in chroni- lar swabbing must be performed with good illumination to cally infected tonsils include an increased proportion of an- reduce contamination of specimens by the microflora of the aerobes [18], an increased representation of anaerobes pos- oropharyn x [ 19]. sessing virulence factors such as encapsulation [7], and an Factors that may result in a variable proportion of anaer- increased level of 0-lactamase production by aerobes such as obes are listed in table 3. These factors are grouped accord- Haemophilus species and S. aureus and anaerobes such as ing to whether the variation is of a superficial or a clinically Bacteroides species [35]. significant nature. Any factors that may represent a source of Bieluch et al. [27] investigated the structural changes asso- variability should be defined and reported as completely as ciated with chronic tonsillitis. Their study of histological sec- possible in all studies. tions indicated that chronic cryptitis was present in patients Notwithstanding the wide variations in the data sets sum- with recurrent tonsillitis; this finding suggests that the key marized in tables 1 and 2, it is still clearly evident that anaer- problem may be bacterial infection of the tonsillar crypts obes play a major role in chronic tonsillitis. The tonsils are rather than of the tonsils themselves. These authors suggest initially colonized with aerobes, which are more virulent and that an initial dose of would eradicate the normal CID 1995;20 (June) Recurrent Sinusitis and Tonsillitis 1515

Table 2. Summary of evidence of the role of anaerobes from studies of recurrent tonsillitis in adults and mixed populations of adults and children.

Percentage of Percentage Anaerobic patients from of organisms species No. of whom organisms that were (in approximate order of [Reference] patients Condition were isolated anaerobes prevalence)

[24] 167 adults Recurrent tonsillitis >80 49 Bacteroides, Fusobacterium [25] 22 adults Excised tonsils* 100/ 58t Prevotella, Bacteroides, Fusobacterium, Peptococcus, Veillonella, Peptostreptococcus, Eubacterium, Downloaded from https://academic.oup.com/cid/article/20/6/1512/477393 by guest on 27 September 2021 Propionibacterium, Actinomyces, Lactobacillus [26] 25/23* Excised tonsils* 100/ 52/63t5 Prevotella, Bacteroides, Fusobacterium, Peptococcus, Veillonella, Peptostreptococcus, Eubacterium, Lactobacillus, Bifidobacterium, Actinomyces, Propionibacterium [27] 10 children Excised tonsils* 100* 33t Bacteroides, Fusobacterium, anaerobic and adults cocci, Veillonella, Actinomyces [28] 28 adults Excised tonsils* 100 46 Bacteroides, Prevotella, Peptostreptococcus, Fusobacterium, Bifidobacterium, Peptococcus, Actinomyces, Eubacterium, Lactobacillus, Propionibacterium [29] 120 children Excised tonsils* 100 NS Prevotella, anaerobic bacteria and adults11 [30] 156 Chronic tonsillitis NS 46 Bacteroides, Fusobacterium, Veillonella, anaerobic cocci [31] 25/21* Excised tonsils* 98/ 42/ Gram-negative rods, Peptostreptococcus, Fusobacterium, anaerobic cocci, Propionibacterium, Leptotrichia

NOTE. NS = not stated. * History of recurrent tonsillitis. / Organisms isolated from both surface and core of tonsils. Indicates ratio of children to adults. *History of recurrent tonsillitis; at time of tonsillectomy, tonsils not clinically inflamed. Anaerobic culture carried out for only 120 of 262 patients studied. flora of the crypts, allowing inhabitation of this ecological studies of sinusitis, which, again, is at least partly due to niche by organisms that are resistant to penicillin. variations in technical practices. In some studies, conditions Chronic sinusitis. Chronic sinusitis causes considerable for anaerobic growth were not maximized, leading to low long-term morbidity: long-term cure rates vary between 29% isolation rates for anaerobes. In many studies, however, ap- and 80% [13]. As is the case with tonsillitis, the proportion of propriate sampling and culture techniques have generally re- anaerobes is higher in chronic episodes of sinusitis than in sulted in the isolation of significant fractions of anaerobes acute episodes (table 4); however, when episodes of sinusitis (table 4). Technical points must be taken into consideration; are compared with episodes of tonsillitis, anaerobic cocci for example, contamination of a sample with nasal flora in- rather than Prevotella species and Bacteroides species are the creases the proportion of aerobic organisms, and samples predominant pathogens. The most commonly isolated an- should therefore be obtained by direct puncture of the sinus. aerobes are anaerobic cocci, pigmented Prevotella species, Culture methods for sinusitis, as well as for tonsillitis, should Porphyrotnonas species, Bacteroides species, and Fusobacter- encourage the growth of strict anaerobes. ium species. When chronic infections are compared with As was noted in studies of tonsillitis, some of the variabil- acute infections in terms of aerobic agents, H. influenzae is ity in isolation of anaerobes that has been reported in studies more prevalent than are pneumococci. of sinusitis is due to technical factors; however, some of this As was noted for studies of tonsillitis, there is wide varia- variability is also likely to be due to clinically significant fac- tion in the types and proportions of organisms isolated in tors such as the microbiology of the different sinuses. The

1516 Nord CID 1995;20 (June)

Table 3. Factors that may affect the ratio of anaerobes to aerobes and desquamation, hyperplasia, and metaplasia of the epithe- isolated in cases of chronic tonsillitis and sinusitis. lium [51]. In addition, leukocyte infiltration, fibrosis, perios- teal hyperplasia, and bone degradation and formation were Factors related to genuine microbiological variations frequently observed. These structural features, which limit Sinusitis and tonsillitis Acute vs. chronic normal drainage, are likely to contribute to the maintenance Purulent vs. nonpurulent of the anaerobic, purulent environment. Untreated vs. previously treated In summary, despite widely varying data, it appears that Dental vs. nondental origin the development of chronic and recurrent tonsillitis and sin- Long-term chronic vs. short-term chronic usitis is associated with increased colonization by anaerobic Underlying pathology (e.g., , ) Age of patient bacteria. Downloaded from https://academic.oup.com/cid/article/20/6/1512/477393 by guest on 27 September 2021 Gender Lifestyle (i.e., diet, exercise, smoker vs. nonsmoker) Geographical location Socioeconomic group Pathogenicity of Anaerobes in Tonsillitis and Sinusitis Seasonal variations Sinusitis Direct Virulent Potential of Anaerobes Sampling of ethmoidal, maxillary, or frontal sinus Intranasal deformity Traditionally, microorganisms were classified as patho- Unilateral vs. bilateral infection gens and nonpathogens. Pathogens were thought to owe Tonsillitis their disease-producing ability to unique characteristics, but Sampling of tonsil surface or tonsil core Sampling of one or both tonsils it is now recognized that most microorganisms that colonize Factors associated with technical variations (i.e., sampling the body have the capacity to cause disease under predispos- techniques and culture methods)* ing circumstances [52]. Many of the anaerobes commonly involved in upper respiratory tract infections possess a num- * Disinfection or not of nasal passages and/or tonsil surface; culture me- ber of virulence factors that confer pathogenicity. Encapsu- dium and time of incubation; and use or not of gram stain. lation has been shown to confer virulence to Bacteroides spe- cies, and capsule production is increased in a number of infectious situations [53]. Increased encapsulation of Bacter- ethmoidal sinuses play an important role in drainage and oides and Prevotella species has been observed in both acute blockage of the other sinuses and thus may be a key factor in and chronic episodes of tonsillitis when the isolates are com- sinusitis [45]; therefore, it may be important to make a dis- pared with those recovered from healthy tonsils [7]. Fusobac- tinction between the microbial flora of the ethmoidal and terium species, also common pathogens in chronic upper re- maxillary sinuses. The maxillary sinuses are the most fre- spiratory tract infections, have been shown to possess the quently studied, largely because of ease of access. One study capability of producing lipopolysaccharides associated with [13] indicated that the microbial flora in patients with virulence as well as neutrophil cytotoxic substances and chronic ethmoidal sinusitis varied from that in patients with DNase [54]. Other virulence factors associated with anaer- chronic maxillary sinusitis (e.g., there were more S. aureus obes include the ability to adhere to mucosal epithelial cells isolates and fewer anaerobes). This finding correlated with and coagulation promotion and spreading factors [1]. the presence of a smaller amount of pus in the ethmoidal Further evidence of the pathogenic role of anaerobes in sinus samples. chronic upper respiratory tract infections has been obtained Microenvironmental conditions are a key factor in the de- with use of an experimental animal model of sinusitis; it was velopment and maintenance of chronic anaerobic sinusitis found that infection with Bacteroides fragilis alone can cause [12]. Aerobic and air-tolerant bacteria appear to colonize the prolonged and severe inflammation of the sinus mucosa of sinus initially; these organisms consume oxygen and alter gas greater severity than that observed in experimental pneumo- tension, resulting in an environment that favors anaerobes coccal sinusitis [51]. In a clinical setting, however, B. fragilis [46, 47]. Once a chronic infection is established, the sinus alone is not considered to be a common cause of chronic provides a good anaerobic environment because inflamma- sinusitis. tion and reduced drainage result in a lower 1 302 and pH; thus, Indirect pathogenicity. The majority of chronic upper re- an optimum oxidation reduction potential for anaerobes ex- spiratory tract infections are polymicrobial; both aerobic and ists [48, 49]. Chronic changes in the mucous membrane pre- anaerobic flora are isolated. Mixed infections enhance the dispose to viscous secretions that are not easily drained into overall virulence of the microbial community because of the the nose. This stagnation is intensified by depressed or ab- synergistic potential of mixtures of aerobic and anaerobic sent ciliary action [50]. Studies with animals models have organisms [55]. investigated the microenvironmental conditions in chroni- One mechanism of synergy that has provoked much inter- cally infected sinuses. These studies reveal ciliary damage est is the protection of susceptible pathogens by fl-lactamase- CID 1995;20 (June) Recurrent Sinusitis and Tonsillitis 1517

Table 4. Summary of evidence of the role of anaerobes in chronic sinusitis.

Percentage of patients from Percentage whom of organisms Anaerobic species No. of organism that were (in approximate [Reference] patients Condition was isolated anaerobes order of prevalence)

[36] Anaerobic cocci, Bacteroides, 83 Chronic sinusitis 75 52 Prevotella, Corynebacterium, Veillonella [37] 66 Acute and 39 39 Peptostreptococcus, Peptococcus, Downloaded from https://academic.oup.com/cid/article/20/6/1512/477393 by guest on 27 September 2021 chronic Veillonella, Propionibacterium, sinusitis Prevotella, Fusobacterium, Bifidobacterium [38] 40 adults Chronic sinusitis 100 19 Anaerobic cocci, Bacteroides, Peptostreptococcus, Veillonella, Fusobacterium, Propionibacterium, Peptococcus [12] 40 children Chronic sinusitis 100 80 Bacteroides, Prevotella, Peptococcus, Fusobacterium, Propionibacterium, Peptostreptococcus, Veillonella, anaerobic cocci, Clostridium, Eubacterium [39] 54 adults Chronic sinusitis >33 42 (Not listed) [9] 35 Chronic sinusitis 70 39 Bacteroides, Prevotella, Fusobacterium, anaerobic cocci [13] 59 Chronic 0 0 None ethmoidal sinusitis [40] 15 adults Chronic sinusitis 38 48 Propionibacterium, Bacteroides, Prevotella, Eubacterium [41] 40 Chronic sinusitis 69 46 Prevotella, Fusobacterium, Bacteroides. Porphyromonas, Peptostreptococcus, Propionibacterium, Veillonella [42] 132 adults Chronic sinusitis NS 22 Peptococcus, Bacteroides, Veillonella [43] 114 adults Acute and NS 12* Bacteroides, Prevotella, Clostridium, chronic Fusobacterium, Eubacterium, sinusitis Peptostreptococcus, Peptococcus [44] 412 Chronic sinusitis NS 26 Propionibacterium, Peptostreptococcus, Prevotella, Fusobacterium

NOTE. NS = not stated. * Percentage of organisms isolated in both acute and chronic cases.

producing organisms, a phenomenon that is described as "in- biotic administration in the presence of BLPB. Penicillin-re- direct pathogenicity" and was forecast >40 years ago [56, sistant organisms have been shown to be capable of protect- 57]. However, the complex nature of this interaction has ing susceptible pathogens from the effects of penicillin [58, made its investigation a considerable challenge. Evidence 59], a finding that indicates the occurrence of indirect patho- that fl-lactamase-producing bacteria (BLPB) can have a pro- genicity in vivo. tective role has emerged from in vitro studies, animal studies, In addition, Maddocks and May produced evidence sug- and clinical studies. gesting the occurrence of indirect pathogenicity in humans Antibiotic-susceptible organisms have been cultured in vi- [57]. In this study, patients with bronchial infection due to tro in the presence or absence of BLPB, followed by the addi- H. influenzae failed to respond to treatment with tion of an antibiotic. These studies have shown that suscepti- because 3-lactamase-producing Enterobacteriaceae were ble organisms can be protected from by BLPB in present in the sputum. Protection via inactivation of ampicil- vitro; for example, /3-lactamase-producing B. fragilis has lin was indicated by the fact that the drug could not be de- been shown to shield streptococci that are normally suscepti- tected in the sputum despite achievement of normal serum ble to penicillin [54]. Animal models have been developed concentrations of the drug. The results of numerous other that assess the ability of susceptible organisms to survive anti- clinical studies have also suggested that protection against 1518 Nord CID 1995;20 (June)

B-lactamases may be provided by a variety of organisms in- monly used antibiotics should be carefully considered. As cluding anaerobes [18, 60-62]. discussed in the previous section, ,B-lactamase-producing or- Ma'ny of the anaerobic bacteria commonly present in ganisms may shield susceptible organisms from B-lactam anti- chronic tonsillitis and sinusitis (e.g., species of Bacteroides, biotics, resulting in indirect pathogenicity. The overall preva- Prevotella, and Fusobacterium) are capable of producing 13- lence of this phenomenon in clinical situations is not known; lactamases [63]. Fusobacteria have been reported to produce however, a number of reports have indicated that administra- a B-lactamase that is active mainly against [24]; tion of penicillin to patients with tonsillitis can lead to selec- this species may therefore represent one of the main indirect tion of B-lactamase-producing organisms [22, 71]. In one pathogens that can shield the group A streptococci from pen- study [72], a high proportion of bacteria isolated from icillins. A correlation has also been noted between ti-lacta- ' healthy volunteers after treatment with penicillin were B-lac- mase activity in saliva and the presence of B-lactamase-pro- tamase producers, including 70% of Bacteroides and Prevo- Downloaded from https://academic.oup.com/cid/article/20/6/1512/477393 by guest on 27 September 2021 ducing Fusobacterium nucleatum strains in the oropharynx. tella species and 43% of Fusobacterium species (the pretreat- Furthermore, resistance to penicillin among strains of Prevo- ment rates for these two groups of species were 23% and 10%, tella tnelaninogenica (formerly Bacteroides melaninogenicus) respectively). B-Lactamase activity was detected in the saliva and Prevotella oralis (formerly Bacteroides oralis) due to 0- of these volunteers and correlated with levels of BLPB [72]. lactamase production is a common finding and is reported to Furthermore, adults with recurrent tonsillitis have higher lev- be increasing in frequency [64]. els of BLPB than do children; this finding is believed to re- BLPB have been isolated from patients with recurrent ton- flect the fact that adults have, on average, received more sillitis [18. 24]. B-Lactamase has also been detected in tonsil- courses of antimicrobials than have children, resulting in a lar tissue of patients with recurrent tonsillitis [25]; this find- shift toward selection of BLPB [26]. fl-Lactamase-producing ing supports the idea that indirect pathogenicity is occurring anaerobic bacteria have been recovered from 45% of patients in this condition. Further evidence for a potential pathogenic with recurrent tonsillitis [73]. role of anaerobes in tonsillitis comes from studies in which Because of global changes in the susceptibilities of anaer- metronidazole was administered to patients with infectious obes, the National Committee for Clinical Laboratory Stan- mononucleosis [65, 66]. Metronidazole was shown to allevi- dards has recommended that susceptibility testing of anaer- ate the clinical symptoms of tonsillar hypertrophy and to obes be undertaken periodically to monitor resistance shorten the duration of fever. Because metronidazole is not patterns. A number of surveys of resistance patterns have active against aerobic bacteria, the most likely mechanism is been undertaken in various parts of the world including Eu- suppression of the oral anaerobic flora and elimination of rope [74], Australia [75], and the United States [71]. Re- their role in the inflammatory response. A role for anaerobic gional variations have been revealed by these studies; for bacteria in recurrent tonsillitis has also been demonstrated example, in monitoring resistance levels of B. fragilis in 15 by recent findings of increased levels of antibodies to P. inter- European countries, it became evident that there was a media (formerly B. intermedius) in patients with recurrent higher level of resistance to and tetracycline in nonstreptococcal tonsillitis [67]. Elevated antibody levels southern Europe than in northern Europe. However, most of are an accepted indication of past bacterial infection; the the surveys revealed shared features, such as the fact that results of this study therefore suggest that P. intermedia can levels of susceptibility to imipenem, cefoxitin, chloramphen- play a pathogenic role in recurrent tonsillitis. icol, metronidazole, clindamycin, and /clavulanic Conversely, it has been suggested that the increase in treat- acid are generally still high. Levels of resistance to penicillins ment failure rates for diseases such as tonsillitis is due to the in cases of tonsillitis due to a mixture of organisms appear to development of resistance to penicillin by streptococci them- vary between 60% and 80% [19, 24, 43]. Further studies of selves [68]. However, one study found no correlation be- resistance levels in anaerobes commonly associated with tween the presence of penicillin-resistant streptococci and chronic tonsillitis and sinusitis, including Prevotella species failure to eradicate the organisms, indicating that indirect and Fusobacterium species, are needed. mechanisms of resistance must be involved [69]. Protection The rate of treatment failures associated with penicillin by B-lactamases may be both direct and indirect. Stefani et therapy is controversial, and it has been suggested that levels al. [70] have suggested that the clinical significance of B-lac- of resistance to penicillin may have been exaggerated [76]. A tamase production probably varies depending on the specific number of the apparent variations in the rates of treatment mixture of microorganisms in each particular incident of in- failure that have been reported may have resulted from dif- fection. Thus, a low failure rate for penicillin therapy can be ferences in methodology. In particular, it has been suggested explained by a relative predominance of susceptible organ- that the inclusion of streptococcal carriers in therapeutic isms rather than BLPB [70]. trials and reinfection after close contact with family members can lead to artificially high estimates of penicillin Therapeutic Options for Chronic Tonsillitis and Sinusitis treatment failure and that the true rate may be closer to 10%- Levels of resistance. To optimize antimicrobial therapy 15% [76]. Therefore, further investigations are merited to the organisms involved and their levels of resistance to com- clarify this question. The comparative clinical trials de- CID 1995;20 (June) Recurrent Sinusitis and Tonsillitis 1519

Table 5. Failure rates in the treatment of recurrent tonsillitis due effective [83]. In another study [84] in which various antibi- to group A /3-hemolytic streptococci with penicillin or amoxicillin/ otics were compared for in vitro activity against both gram- clavulanic acid. positive and gram-negative anaerobic bacteria, the overall No. of patients for whom treatment efficacy rates, in descending order, were as follows: ticarcil- failed/total no. of patients treated (%) lin/clavulanic acid, 99.7%; amoxicillin/clavulanic acid, 97.4%; chloramphenicol, 97.4%; metronidazole, 95.4%; pi- [Reference]/year Penicillin Amoxicillin/clavulanic acid peracillin, 92.4%; ticarcillin, 91.4%; clindamycin, 87.8%; ce- fotetan, 81.2%; cefazolin, 63.0%; cefuroxime, 60.4%; erythro- [78] 1988 17/24 (71) 2/21 (9) [82] 1989 6/21 (30) 0/20 (0) mycin, 57.8%; penicillin, 57.1%; and doxycycline, 52.1%. [30] 1991 16/75 (21) 1/77 (I) There is a range of $-lactamase inhibitors, and their Downloaded from https://academic.oup.com/cid/article/20/6/1512/477393 by guest on 27 September 2021 various characteristics should be considered because of the increasing prevalence of BLPB providing extended-spectrum coverage and the different susceptibilities of organisms pro- scribed in the next section give an empirical indication of the ducing the various 13-lactamases to different (3-lactamase most suitable therapies currently available. inhibitors. Hedberg et al. [85] compared three 13-lactamase Requirement for broad-spectrum antimicrobial coverage. inhibitors—clavulanic acid, sulbactam, and tazobactam- As discussed in previous sections, it is difficult to evaluate with respect to their effect on f3-lactamases from three anaer- accurately the organisms involved in chronic tonsillitis and obes—Bacteroides unifiymis, Clostridium butyricum, and F. sinusitis and their levels of resistance. However, the results of nucleatum. Tazobactam was the most effective agent overall. the clinical trials discussed below indicate that optimal thera- Clavulanic acid and sulbactam were more effective against B. peutic benefits, including protection from /3-lactamases, are uniformis than against C. butyricum and F. nucleatum [85]. provided by broad-spectrum coverage. The bacteriologic Other broad-spectrum, B-lactamase-resistant antimicro- findings described previously are consistent with the im- bials that should be effective against the organisms involved proved efficacy of broad-spectrum antibiotics because of the in chronic tonsillitis and sinusitis include clindamycin, linco- heterogeneous mixture of bacteria (i.e., aerobes, gram-nega- mycin, chloramphenicol, cefoxitin, and imipenem [86]. In a tive anaerobes, and gram-positive anaerobes) involved. In recent study, the third-generation cefixime addition, combining a fl-lactamase inhibitor with a 13-lactam was shown to be effective in only -50% of adult patients antibiotic can further expand the spectrum of a tried and trusted f3-lactam antibiotic. with acute or chronic sinusitis [43]. However, unlike the anti- In a clinical trial Boccazzi et al. [77] compared amoxicil- biotics mentioned above, cefixime is not active against gram- lin/clavulanic acid with as treatment for 20 negative anaerobes, although it is stable in the presence of pediatric patients with upper respiratory tract infections, in- 0-lactamase. As mentioned previously, metronidazole is ef- cluding tonsillitis and sinusitis. Amoxicillin/clavulanic acid fective against the anaerobic bacteria likely to be involved in was highly effective: the organisms were eradicated in 90% of chronic tonsillitis and sinusitis but is ineffective against aero- cases and the agent was well-tolerated. This trial indicates bic bacteria; therefore, it is only useful as a component of a that the use of a fl-lactamase inhibitor enhances the efficacy combination regimen (e.g., in combination with penicillin or of fl-lactam antibiotics and further confirms the theory that erythromycin) for the treatment of mixed aerobic and anaer- /3-lactamase production is a key mode of resistance among obic infections [86]. organisms that cause chronic tonsillitis and sinusitis. Other Brook has stated that "early and vigorous antimicrobial studies support the efficacy of amoxicillin/clavulanic acid in therapy, directed at both aerobic and anaerobic bacteria pres- the treatment of both tonsillitis and sinusitis [23, 28, 78-80]. ent in these mixed infections, may abort the infection before Data from studies that indicate the usefulness of amoxycil- the emergence of encapsulated strains that contribute to the lin/clavulanic acid in the treatment of tonsillitis [81] are sum- chronicity of infection" [35]. However, other investigators marized in table 5. have pointed out that treating all chronic upper respiratory The clinical efficacy of amoxicillin/clavulanic acid for the tract infections with broad-spectrum antibiotics is expensive treatment of chronic upper respiratory tract infection is sup- and may be unnecessary. Furthermore, certain drawbacks ported by the results of in vitro studies of its kill kinetics have been associated with the use of broad-spectrum antibi- when the drug was tested against a variety of organisms, in- otics, such as disturbance of the normal oral and intestinal cluding gram-negative and gram-positive anaerobes, com- microflora [87]; for example, in a recent study healthy volun- monly involved in chronic tonsillitis and sinusitis [83]. Pi- teers were given cefpodoxime proxetil or amoxicillin, and peracillin and ticarcillin alone were not always effective the impact of the agents on the oral and intestinal microflora against species of Bacteroides and Prevotella, even at suprain- was evaluated [88]. Administration of cefpodoxime proxetil hibitory concentrations, whereas the combinations of ticar- induced overgrowth of enterococci, yeasts, and Clostridium cillin/clavulanic acid and amoxicillin/clavulanic acid (a )3- difficile in the fecal flora, while administration of amoxicillin lactam agent plus a (3-Iactamase inhibitor) were both induced overgrowth of new-colonizing, amoxicillin-resistant 1520 Nord CID 1995;20 (June)

organisms in the fecal flora. Only minor alterations in the sistant organisms in patients with chronic infections [1]. oral microflora were associated with both treatments. Drainage of the sinus is important in the treatment of chronic Because of the potential disadvantages of antibiotic admin- sinusitis and in many cases is an integral part of manage- istration, it is important to evaluate the organisms involved ment. Sinusitis predisposes to the development of intracra- in individual cases so that appropriate therapy can be applied nial abscesses. Tissue necrosis and invasion of blood vessels to the specific incident of infection. However, given the diffi- by anaerobes facilitates intracranial infection [93]. The recov- culties in evaluating pathogens in chronic upper respiratory ery of penicillin-resistant organisms including B. fragilis, Pre- tract infections and the evidence for the involvement of votella species, and Porphyromonas species from patients polymicrobial flora, the use of antimicrobials for broad-spec- with sinusitis is an indication for antimicrobial agents that trum coverage would currently appear to be the most advis- penetrate the blood-brain barrier such as chloramphenicol or able approach in cases of chronic or recurrent tonsillitis and metronidazole (penicillin should be used in addition to met- Downloaded from https://academic.oup.com/cid/article/20/6/1512/477393 by guest on 27 September 2021 sinusitis. A meta-analysis of the use of and ronidazole for coverage of aerobic and microaerophilic strep- penicillins in patients with tonsillitis that was recently under- tococci). Surgical drainage may be required—some reports taken by Pichichero and Margolis [89] indicated that one indicate that delay in surgical drainage and decompression penicillin-associated bacteriologic treatment failure could be can be associated with high morbidity and mortality [93, 94]. prevented for every 12-13 patients treated with an antibiotic However, other studies have illustrated that brain abscesses not affected by f3-lactamase. that develop in the early phase of cerebritis may respond to However, further investigation is required to define the antimicrobial therapy without surgical drainage [95]. optimum choice of therapy for chronic tonsillitis and sinusi- Cryosurgery may be undertaken to treat tonsillitis. In cases tis. There is a paucity of comparative clinical data for evalua- where eradication is not achieved and serious clinical symp- tion of the most effective antibiotic regimens; the findings of toms remain, major surgical intervention (i.e., elective ton- key comparative trials undertaken to date are summarized in sillectomy) may be required; however, this procedure may be table 6. It is essential that further trials are conducted to avoided because of possible potential complications. Simi- compare the cure rate of various antibiotics when they are larly, ethmoidectomy should only be undertaken as a last administered for these infections, and a double-blind design resort. should be used where possible. In addition, the comparative efficacy of placebo vs. antibiotic treatment for chronic tonsil- Future Improvements in the Treatment of Chronic litis and sinusitis requires further evaluation. The final Tonsillitis and Sinusitis choice of treatment must also be based on cost, particularly given the large proportion of cases of chronic tonsillitis and Accurate assessment of the organisms involved. It is diffi- sinusitis and the resultant substantial burden of treatment on cult to define precisely the species involved in chronic upper health care budgets. respiratory tract infections and to ascertain their resistance Appropriate dosing strategies. It is important to try to de- characteristics. The development and application of molecu- fine a dosing strategy that will minimize the possibility of lar methods probably represent the most logical approach to selection of resistant strains. Controversy exists as to whether these problems [96]. Such techniques should allow identifi- the emergence of resistant strains is more likely to be encour- cation of the microbial species involved as well as identifica- aged by the short-term use of high doses or the long-term use tion of strains; a detailed molecular profile of resistance of lower doses. In Scandinavia, high doses of penicillin have should be ascertained. been used for the treatment of streptococcal tonsillitis [92], As mentioned previously, it is difficult to evaluate anaer- and significant rates of clinical treatment failures have been obes precisely in terms of numbers of organisms or cfu per observed in association with this regimen. As discussed ear- gram of tissue, the ratio of each species to another, or the lier, this could be due to selection of fl-lactamase-producing ratio of anaerobes to aerobic species. Molecular techniques organisms such as Bacteroides species. A clinical trial com- could help to categorize precisely (i.e., at the genetic level) paring the efficacy of the high-dose penicillin regimen with the organisms involved and also allow more-precise quantifi- that of the low-dose penicillin regimen for the treatment of cation of each species; this information would allow therapy tonsillitis yielded inconclusive results. With respect to the to be targeted more precisely at specific pathogens. duration of therapy, there is some evidence that extension The growing levels of resistance among anaerobes have beyond 10 days, if clinically warranted, results in a better increasingly led to demands that testing be undertaken on a rate of cure and clinical improvement [62]. However, further routine basis. However, there are particular problems in pro- studies are required to clarify the question of optimum dos- ducing accurate results of susceptibility testing of anaerobes, ing strategies. and no consensus on the procedure used and the interpreta- Surgical intervention. In addition to vigorous antimicro- tion of results has been reached [97]. A number of authors bial therapy, minor surgical procedures such as drainage and have emphasized the need for more convenient and reliable debridement are often required to eliminate reservoirs of re- techniques for susceptibility testing of anaerobes [98, 99]. CID 1995;20 (June) Recurrent Sinusitis and Tonsillitis 1521

Table 6. Data from comparative clinical trials assessing the efficacy of different antibiotic regimens for the treatment of chronic and/or recurrent tonsillitis and sinusitis.

Treatment; Duration of no. of patients Study treatment No. of clinically cured/no. Statistical

[Reference] design Infection Regimen (d) patients of patients treated significance

[23] Prospective, Recurrent Amoxicillin/clavulanic acid 10 20 Amoxicillin/clavulanic acid;

randomized, tonsillitis (40 mg/[kg • d] in four 16/18 (1 year of follow-

single blinded divided doses) up) P < .005 Penicillin VK (40 mg/ 20 Penicillin; 8/19 (,10 mo) [kg • d]; suspension or Downloaded from https://academic.oup.com/cid/article/20/6/1512/477393 by guest on 27 September 2021 tablets in four divided doses)

[30] Prospective, Chronic Amoxicillin/clavulanic acid 10 156 Amoxicillin/clavulanic acid;

randomized, tonsillitis (three times per day; 500 76/77

open mg amoxicillin/125 mg clavulanic acid) P < .001 Penicillin V (three times Penicillin; 56/75 per day; 1 million units of phenoxypenicillin) [43] Prospective, Maxillary Cefixime once daily; 400 10-14 63 Cefixime; 27/53

randomized, sinusitis mg 10-14 51 Amoxicillin; 23/49 Not significant

open (acute and Amoxicillin (three times

chronic) per day; 500 mg)

[77] Prospective, Recurrent Amoxicillin/clavulanic acid 9.5 10 Amoxicillin/clavulanic acid; randomized, tonsillitis, (twice daily; dose 10/10

open sinusitis, and dependent on body

otitis media weight) P < .001 Erythromycin (three times 9.7 10 Erythromycin; 0/10 per day; dose dependent on body weight)

[90] Prospective, Recurrent Penicillin (dose not NS 15 Penicillin; 2/14

randomized, tonsillitis specified)

open Erythromycin (dose not NS 15 Erythromycin; 8/14 NS specified) Clindamycin (dose not NS 15 Clindamycin; 14/15 specified)

[91] Prospective, Streptococcal Pencillin V (80,000 U/ 10 39 Penicillin V; 28/39

randomized, [kg • d] in four divided P = .0015

open doses) Pencillin V (80,000 U/ 10 40 Penicillin V plus rifampin; [kg • d] in four divided 40/40 doses) with rifampin (20 mg/[kg • d] once a day for the last 4 days)

NOTE. NS = not stated.

Several techniques have recently been developed that may is required to facilitate future molecular diagnosis. The mo- prove useful, such as the spiral gradient endpoint method lecular basis of resistance in anaerobes involved in upper [100]. In the future, molecular methods for assessing suscep- respiratory tract infections such as gram-negative pigmented tibility are likely to become more prevalent. Such techniques anaerobes has been studied preliminarily [101]. However, in would be quicker than conventional techniques and could this study, no correlation between specific plasmids and phe- provide more-detailed information (e.g., the identification of notypic characteristics, such as antibiotic resistance, was the genotypes associated with specific antibiotypes). seen. Further studies on the genetic basis of antibiotic resis- At present, the genetic basis of resistance in many of the tance in anaerobic bacteria are warranted. anaerobes involved in chronic tonsillitis and sinusitis is not Therapeutic options for the future. Future approaches clear; whether resistance is plasmid- or chromosome- should include judicious use of currently available antibi- mediated has not been determined, and further investigation otics and continuous development of new antibiotics that 1522 Nord CID 1995;20 (June) allow clinicians to be prepared for resistance before it current therapeutic options and future directions in diagnosis emerges by arming them with "emergency" antibiotics that and therapy have been highlighted. the general population has not been exposed to. The avail- Finegold [1] stated in 1977 that "development of resis- ability of drugs to which exposure has been minimal is the tance has not been a major problem among anaerobes to rationale for continuous development and testing of new an- date" [1]. However, because of complacency concerning the timicrobial therapies; a number of drugs have recently been administration of antibiotics, these words can no longer be developed that show promise against the types of anaerobes stated with confidence. One hopes that with respect to po- involved in chronic tonsillitis and sinusitis [102-104]. tentially problematic diseases such as chronic tonsillitis and It must be borne in mind that in addition to 0-lactamase sinusitis, better evaluation of microflora, awareness and un- production, other clinically significant mechanisms of resis- derstanding of resistance patterns, and judicious use of antibi- tance exist, including production of other drug-inactivating otics will ensure that this emerging problem may be con- Downloaded from https://academic.oup.com/cid/article/20/6/1512/477393 by guest on 27 September 2021 enzymes, alteration of target proteins, and the inability of tained and controlled. drugs to penetrate the bacterial cell wall [99]. The signifi- cance of other resistance mechanisms is illustrated by data from Tanz et al. [105], who showed that the bacteriologic References treatment failure rate in cases of streptococcal pharyngitis 1. Finegold SM. 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Nord CE, Lindmark A, Persson I. In vitro activity of L 627 against 81. Brook I. Indirect pathogenicity. Infect Dis Pract 1994; 3(suppl):S21- anaerobic bacteria. Eur J Clin Microbiol Infect Dis 1992; 11:757- 7. 60. 82. Brook I. Treatment of recurrent tonsillitis, penicillin vs. amoxicillin 104. Nord CE, Lindmark A, Persson I. In vitro activity of the new quino- plus clavulanic-potassium. J Antimicrob Chemother 1989; 24:221- lone BAY y 3118 against anaerobic bacteria. Eur J Clin Microbiol 33. Infect Dis 1993;12:640-2. 83. Dubreuil L, Houcke I, Romond C. Kill kinetics studies of penicillins 105. Tanz RR, Shulman ST, Sroka PA, Marubio S, Brook I, Yogev R. Lack alone or in combination with clavulanic acid or tazobactam against of influence of /3 lactamase producing flora on recovery of group A anaerobic bacteria [abstract no P3.124]. In: Program and abstracts streptococci after treatment of acute pharyngitis. J Pediatr of the 17th International Congress on the Management of Infection 1990;117(6):859-63. (Berlin). Munich: Futuramed, 1992. 106. Crowe CC, Sanders WE Jr, Longley S. Bacterial interference. II. Role 84. Pierard D, De Meyer A, Rosseel P, et al. In vitro activity of amoxycil- of the normal throat flora in prevention of colonization by group A lin plus clavulanic acid compared with that of other antibiotics Streptococcus. J Infect Dis 1973;128:527-32. against anaerobic bacteria. Acta Clin Belg 1989;44:228-36. 107. Roos K, Holm SE, Grahn E, Lind L. Alpha streptococci as supplemen- 85. Hedberg M, Lindqvist L, Tuner K, Nord CE. Effect of clavulanic acid, tary treatment of recurrent streptococcal tonsillitis: a randomized sulbactam and tazobactam on three different /3-lactamases from placebo controlled study. Scand J Infect Dis 1993;25:31-5.