SUPPLEMENT ARTICLE

Current Management of Acute Bacterial Rhinosinusitis and the Role of Moxioxacin

Episodes of acute rhinosinusitis are common among adults and are associated with a signicant amount of morbidity. The symptoms of rhinosinusitis are nasal drainage, congestion, and sinus pressure. A bacterial sinus infection is more likely if these symptoms worsen after 57 days or do not improve after 1014 days. The majority of bacterial episodes have been associated with Streptococcus pneumoniae and Haemophilus inuenzae. In the current era of increasing resistance to b-lactams and macrolides, treatment guidelines have been formulated worldwide to assist clinicians in the selection of antibacterials. According to one model, the following antibacterials are most likely to provide desired outcomes (90%92% predicted clinical efcacy) for adults: respiratory uoroquinolones (i.e., moxioxacin, gatioxacin, and levooxacin), ceftriaxone, and highdose amoxicillin-clavulanate (4 g of amoxicillin/day and 250 mg of clavulanate/day). Although the role of the uoroquinolones in the treatment of this condition is evolving, uoroquinolones are often recommended as second-line therapy or as rst-line therapy for selected patients (e.g., those who received antibacterials in the previous 46 weeks or adults with moderate-to-severe disease). Acute bacterial rhinosinusitis (ABRS) is a bacterial infection involving the paranasal sinuses and is usually preceded by a viral upper respiratory tract infection (URTI; i.e., the common cold) or an acute exacerbation of an allergic disorder [1]. In 1996, the American Academy of OtolaryngologyHead and Neck Surgery Foundation developed working denitions of sinusitis in an attempt to standardize communication among health-care providers and researchers [2]. Because sinusitis is generally preceded by rhinitis and rarely occurs without concurrent rhinitis, the more appropriate term for this condition is rhinosinusitis. Bacterial superinfection may occur at any time point after viral infection but is generally assumed to have occurred if symptoms have persisted for 110 days or have worsened after 57 days [2]. Because diagnosing ABRS can be difcult, the misuse and overuse of antibacterials for the treatment of URTIs has become a major problem throughout the world, as patients and clinicians incorrectly overdiagnose bacterial disease. The Centers for Disease Control and Prevention have reported that there are 50 million unnecessary antibiotic prescriptions for the common cold and other viral infectionsagainst which antibacterials are not effectivewritten in the United States [3]. Recently, the US Food and Drug Administration began requiring that the labeling for systemic antibacterials include statements about the unnecessary use of antibacterials and the association between such use and the increase in drugresistant bacterial strains. By 1996 estimates, 9% of all antibiotic prescriptions in the United States are written for the treatment of ABRS [4]. The present article briey reviews the pathophysiology, etiology, clinical presentation, and diagnosis of ABRS. Treatment options for ABRS in an era of antibiotic resistance are also presented, with a discussion of the role of uoroquinolones, moxioxacin in particular, in the treatment of this infection. PATHOPHYSIOLOGY AND CLINICAL PRESENTATION OF ABRS A viral URTI usually precedes ABRS. Allergy, another inammatory condition of the nose and paranasal siAcute Bacterial Sinusitis and Quinolones CID 2005:41 (Suppl 2) S167

Reprints or correspondence: Dr. Jack B. Anon, Dept. of Otolaryngology, University of Pittsburgh School of Medicine, 3580 Peach St., Erie, PA 16508 (janonmd @velocity.net). Clinical Infectious Diseases 2005; 41:S16776 2005 by the Infectious Diseases Society of America. All rights reserved. 1058-4838/2005/4102S2-0008$15.00

nuses, may also predispose individuals to develop ABRS. Viruses that cause infections of the upper airway include rhinovirus, coronavirus, inuenza A and B viruses, parainuenza virus, respiratory syncytial virus (RSV), and adenovirus. Most of these viral infections occur during the early fall to early spring, manifesting as a common cold, and the incidence of sinusitis is higher during this time [1]. Viral URTI stimulates increases in inammation and in the local immune response of the nasopharynx and surrounding mucosa. Some viruses, such as inuenza virus, produce signicant mucosal damage. Others promote the local production of cytokines and other inammatory mediators, leading to the signs and symptoms of the common cold (i.e., viral URTI) [5]. Numerous cytokines and proinammatory mediators (e.g., IL-1b, IL-2, IL-6, IL-8, TNF-a, histamine, leukotriene C4, and prostaglandins) are up-regulated during ABRS episodes. Viruses have a suppressive effect on the function of neutrophils, macrophages, and lymphocytes [5], including diminished adherent, chemotactic, phagocytic, oxidative, secretory, and bactericidal functions of neutrophils. Viruses also decrease the function of macrophages and lymphocytes, resulting in patients with viral URTIs being generally more vulnerable to secondary overgrowth and subsequent bacterial infection by pathogens that colonize the nasopharynx, such as Streptococcus pneumoniae and Haemophilus inuenzae. Colonization with nontypeable H. inuenzae is signicantly affected by concurrent infection with RSV; however, the site of bacterial attachment is not known. The mechanism of attachment involves up-regulation of expression of epithelial cellsurface receptors, including CEACAM1 and intercellular adhesion molecule1 [5]. Attachment sites for S. pneumoniae may also be exposed. As for the role that allergy plays in ABRS, Blair et al. [6] instilled S. pneumoniae during ongoing nasal allergic inammation in a mouse model and found that allergy augments the infection and the resultant inammatory response. They also showed that allergy alone or allergen exposure did not enhance the sinus infection, which suggests that local inammation is important. The scientic basis for the role that allergy plays in ABRS includes the following theories: release of mediators from mast cells during an allergic reaction causes greater transudation of uid and increased proliferation of bacteria in the sinus cavities; inammatory mediators released by eosinophils during an allergic reaction expose epithelial S. pneumoniae binding sites; and ciliary transport from the sinuses altered by allergic inammation reduces clearance of bacteria. The symptoms of rhinosinusitis are a consequence of the activation of inammatory pathways and the parasympathetic nervous system. Fever, myalgia, and pharyngitis frequently associated with a viral URTI usually resolve by approximately day 5 [5]. Nasal congestion, postnasal drainage, and cough may persist into the second and third weeks. Notably, a change in
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the color of the nasal discharge does not suggest the presence of bacterial infection [5]. To determine the point in time if and when a secondary bacterial infection develops becomes a clinical and diagnostic dilemma, Lacroix et al. [7] studied 265 patients with URTIs and reported that there are no distinct signs or symptoms in patients with mild-to-moderate clinical presentations that predict the presence of pathogenic bacteria. DIAGNOSIS OF ABRS According to the ABRS treatment guidelines of the Sinus and Allergy Health Partnership (SAHP), a clinical diagnosis of ABRS may be made when URTI symptoms (e.g., nasal congestion, facial pressure and/orpain [especially unilateral], and postnasal drip) worsen after 57 days or do not improve after 1014 days [5]. However, the identication of specic signs and symptoms at clinical examination does not appear to reliably predict bacterial infection [5]. Radiography provides only moderate sensitivity (76%) and moderate specicity (79%) for the diagnosis of ABRS [8]. A negative result of plain-lm radiography has a better predictive value than does a positive results. Plain-lm radiographs are valuable for visualizing the frontal and maxillary sinuses but are not useful if infection is ethmoid in origin; plain-lm radiographs also do not reveal the extent of disease [5]. Furthermore, abnormal ndings on plain-lm radiographs do not differentiate viral from bacterial disease. In a group of patients with suspected bacterial ABRS and positive ndings on radiographs, only 50% of sinus taps yielded pathogenic bacteria [9]. CT and MRI are not recommended for most patients with ABRS but may be valuable for patients with complicated episodes [5]. Sinus puncture, with aspiration and culture, is the reference standard for identifying bacterial episodes, although it is basically a research tool. Some experts believe that positive results of bacteriological cultures of nasopharyngeal aspirates best identify those patients who may benet from antibiotic treatment [7]. This idea was also proposed by Kaiser et al. [10]; of 288 patients with URTIs, 20% had nasopharyngeal cultures positive for H. inuenzae, Moraxella catarrhalis, or S. pneumoniae. Among patients with proven bacterial infections, the rate of clinical cure among patients given amoxicillin-clavulanate therapy was 10 times higher, and the symptom scores on day 5 were signicantly lower, compared with those for patients given placebo [10]. Additional studies are needed to validate this theory. Talbot et al. [11] reported that, when cultures obtained by rigid nasal endoscopy were compared with those obtained by sinus puncture and aspiration, endoscopic cultures had a sensitivity of 85.7%, a specicity of 90.6%, a positive predictive value of 80%, a negative predictive value of 93.5%, and accuracy of 89.1%. Their study, which is the largest to date, demonstrated

that endoscopic sampling compares favorably with puncture and aspiration for identifying the major pathogens that cause ABRS. In summary, a diagnosis of rhinosinusitis is typically made at clinical presentation, with bacterial episodes likely if symptoms persist for 11 week. Imaging techniques are not indicated for most cases seen in routine clinical practice, and microbiological sampling techniques are useful for clinical investigations, albeit with caveats about their sensitivity. ETIOLOGY AND ISSUES OF RESISTANCE The major pathogens responsible for ABRS in adults are S. pneumoniae and H. inuenzae. Although the reported percentages of each vary, in a recent tap study [9], we identied 133 S. pneumoniae (33%) and 116 H. inuenzae (29%) isolates (total, 399 isolates). The use of conjugate pneumococcal vaccine in the pediatric population may be responsible for an increase in the prevalence of H. inuenzae in adults with rhinosinusitis. Surveillance studies are used to monitor changes in resistance among the major pathogens. The Alexander Project is a surveillance network that examines the susceptibility of pathogens involved in community-acquired respiratory tract infections in adults [12]. In the most recent report, 8882 isolates of S. pneumoniae, 8523 isolates of H. inuenzae, and 874 isolates of M. catarrhalis were collected during 19982000 from 26 countries. Among S. pneumoniae isolates, the worldwide prevalence of resistance to penicillin (MIC, 2 mg/L) was 18.2%, and that of resistance to macrolides (erythromycin MIC, 1 mg/L) was 24.6%. In the United States, 37% of 2432 S. pneumoniae isolates demonstrated resistance to penicillin. The worldwide prevalence of uoroquinolone-resistant S. pneumoniae (ooxacin MIC, 8 mg/L) was low (1.1%) [12]. The prevalences of blactamaseproducing H. inuenzae and M. catarrhalis isolates are 16.9% and 92.1%, respectively. In this surveillance study, both H. inuenzae and M. catarrhalis were highly susceptible to the tested uoroquinolones (199.8%). Another surveillance networkthe TRUST Studyexamined global changes in resistance patterns among common sinus pathogens. Sahm et al. [13] reported that, for S. pneumoniae, increases in resistance to penicillin between 1999 and 2003 were detected only in China (from 2.3% to 25.0%) and Thailand (from 39.3% to 60.9%). Increases in resistance to azithromycin were detected in China (from 66.4% to 84.4%), Germany (from 13.4% to 28.8%), Hong Kong (from 44.6% to 75.5%), Thailand (from 47.6% to 65.2%), and the United Kingdom (from 9.8% to 29.4%). Multidrug resistance increased in China (from 2.3% to 21.9%); in other countries, the incidence remained similar to incidences reported for 20012002. For all countries combined, rates of resistance to levooxacin remained low during the 3 study years: 0.6% (for 19992000), 0.7% (for 20012002), and 1.0% (for 2003). For H. inuenzae, between 1999 and 2003,

increases in production of b-lactamase were detected in France (from 33.7% to 37.2%), Germany (from 6.9% to 20.3%), South Africa (from 7.4% to 11.2%), and the United Kingdom (from 11.3% to 25.9%). In the same study [13], S. pneumoniae sinus isolates collected during 3 consecutive respiratory tract infection seasons in the United States were tested against a panel of antimicrobials by use of NCCLS broth microdilution. Among 131 S. pneumoniae sinus isolates collected during 20002003, 52.6% of isolates were susceptible to penicillin, 59% were susceptible to azithromycin and erythromycin, 60.3% were susceptible to cefuroxime, 85.9% were susceptible to amoxicillin-clavulanate, and 99.4% were susceptible to levooxacin. During 2003, levooxacin, gatioxacin, and moxioxacin demonstrated equivalent susceptibilities (100%). From 2000 to 2003, only 3 levooxacinresistant isolates (0.6%) were identied. Multidrug-resistant phenotypes (i.e., those resistant to 3 antimicrobial classes) accounted for 23.5% of isolates during 20002003. Resistance to penicillin, azithromycin, and trimethoprim-sulfamethoxazole (TMP-SMZ) was the most common multidrug-resistant phenotype, and 198% of strains with this phenotype were susceptible to levooxacin. ANTIMICROBIAL THERAPY AND TREATMENT GUIDELINES Although it remains difcult to determine which patients should receive antimicrobial therapy, antibacterials are considered to be benecial for treatment of known or suspected bacterial episodes of sinusitis [1, 5]. The landmark Agency for Health Care Policy and Research 1999 guidelines identied only 6 studies that met the criteria for a meta-analysis evaluating the benets of antibacterials, versus no antibacterials, for the treatment of ABRS [8]. As shown in gure 1, antibacterials were signicantly more effective, clinically curing one-third more cases and reducing treatment failures by one-half, compared with placebo [8]. According to French experts, antibiotic treatment has modied the treatment of acute purulent maxillary sinusitis, and indications for drainage and washing of the paranasal sinuses are now rare [20]. Historical data from the preantibiotic era also conrm that the treatment of acute disease with antibacterials has reduced the thrombophlebitic, CNS, and orbital complications of purulent sinusitis. Although data support the use of antibacterials, the development of resistance in several key respiratory pathogens has led to new paradigms for treating ABRS. Antibacterials once approved by the US Food and Drug Administration may no longer have a pharmacokinetic/pharmacodynamic prole needed to provide optimal bacterial killing. Treatment guidelines for the management of ABRS have been developed by several expert groups throughout the world. A brief review of their ndings and recommendations is presented below.
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Figure 1.

Meta-analysis of studies favoring vs. those not favoring the use of antibacterials to treat acute bacterial rhinosinusitis episodes [8]

US guidelines. In 2000, the SAHP published guidelines that thoroughly reviewed the various aspects of ABRS, with emphasis on appropriate antibiotic choices in an era of resistance [21]. Work on these guidelines began after the Centers for Disease Control and Preventions Drug-Resistant Streptococcus pneumoniae Therapeutic Working Group published an article on the treatment of acute otitis media in an era of resistant pneumococci [22]. The SAHP recently revised these guidelines in 2004, to consider further changes that had occurred in antibiotic resistance patterns [5]. The current SAHP treatment guidelines are based on a mathematical model of ABRS treatment that predicts the bacteriological and clinical efcacy of antibacterials according to pathogen distribution, rates of spontaneous resolution without treatment, and in vitro microbiological activity at pharmacokinetic/pharmacodynamic break points [23]. According to this model, after the best data are used, antibacterials can be placed into the following relative rank order according to their predicted clinical efcacy in adults: 90%92%, the respiratory uoroquinolones (i.e., moxioxacin, gatioxacin, and levooxacin), ceftriaxone, and high-dose amoxicillin-clavulanate (4 g of amoxicillin/day and 250 mg of clavulanate/day); 83%88%, high-dose amoxicillin (4 g/day), amoxicillin (1.5 g/day), cefpodoxime proxetil, cexime (on the basis of H. inuenzae and M. catarrhalis coverage), cefuroxime axetil, cefdinir, and TMP-SMZ; 77%81%, doxycycline, clindamycin (on the basis of gram-positive coverage only), azithromycin, clarithromycin and erythromycin, and telithromycin; and 65%66%, cefaclor and loracarbef (gure 2). The predicted rate of spontaneous resolution among patients with a clinical diagnosis of ABRS is 62%. The 2004 SAHP guidelines divide patients with ABRS into 2 general categories: (1) those with mild disease who have not received antibacterials within the past 46 weeks or (2) those
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with mild disease who have received antibacterials within the past 46 weeks and those with moderate disease, regardless of recent antibiotic exposure [5]. The terms mild and moderate are not further dened, leaving the denition of severity up to the clinical judgment of the health-care provider. Patients who have received recent antibiotic therapy or those with moderate disease are more likely to be infected with a resistant organism; for these patients, there is also more concern about the long-term consequences if treatment fails. Current SAHP recommendations for initial therapy for adult patients with mild disease who have not received antibacterials in the previous 46 weeks include the following options: amoxicillin-clavulanate (1.754 g of amoxicillin/day and 250 mg of clavulanate/day), amoxicillin (1.54 g/day), cefpodoxime proxetil, cefuroxime axetil, or cefdinir [5]. TMP-SMZ, doxycycline, or macrolides-azalides-ketolides (i.e., azithromycin, clarithromycin, erythromycin, or telithromycin) may be considered for patients with allergies to b-lactams (table 1). If there is no improvement after 72 h, patients should have treatment switched to a respiratory uoroquinolone, high-dose amoxicillin-clavulanate, ceftriaxone (12 g/day for 5 days), or combination therapy (e.g., high-dose amoxicillin or clindamycin plus cexime or rifampin). Adults with mild disease who have received antibacterials during the previous 46 weeks or adults with moderate disease may be treated with respiratory uoroquinolones or high-dose amoxicillin-clavulanate. However, the SAHP warns that the widespread use of respiratory uoroquinolones for patients with milder disease may promote resistance of a wide spectrum of organisms to this class of agents. Ceftriaxone or combination therapy with adequate coverage for gram-positive and -negative bacteria may also be considered (i.e., high-dose amoxicillin or clindamycin plus cexime or rifampin).

Figure 2. Marchant plot for antibacterials used to treat acute bacterial rhinosinusitis in adults. *Respiratory quinolone (i.e., gatioxacin, levooxacin, or moxioxacin). Amox, amoxicillin; clav, clavulanate; HD, high dose; TMP-SMZ, trimethoprim-sulfamethoxazole. Reprinted with permission from the American Academy of OtolaryngologyHead and Neck Surgery Foundation [5].

French guidelines. French treatment guidelines recommend the following rst-line agents for the treatment of adult patients with ABRS: amoxicillin-clavulanate, second-generation oral cephalosporins (cefuroxime axetil), some third-generation oral cephalosporins (cefpodoxime proxetil), and pristinamycin (a naturally occurring streptogramin not available in the United States) [20]. They also recommend that uoroquinolones active against S. pneumoniae should be reserved for patients for whom rstline treatment fails. The French Agency for Sanitary Safety of Health Products also states that amoxicillin and macrolides are no longer recommended rst-line treatments for ABRS. Per these guidelines, a 710-day antimicrobial treatment course is advised. These guidelines also suggest that short-course adjunctive corticosteroid therapy may be benecial for some patients. German guidelines. The German sinus treatment guidelines recommend amoxicillin as empirical rst-line therapy [24]. Many alternatives are listed in those guidelines, including b-lactam/b-lactamase inhibitor combinations, second-generation oral cepahlosporins, macrolides, ketolides, TMP-SMZ, doxcycline, and clindamycin. For patients with more-severe disease (risk factors) or for whom rst-line therapy failed, amoxicillin-clavulanate, second-generation cephalosporins, or, alternatively, respiratory uoroquinolones or third-generation cephalosporins are the recommended therapies. Spanish guidelines. Treatment guidelines for ABRS have also been published by the Spanish Society of Chemotherapy and the Spanish Society of Otorhinolaryngology and Cervico-Facial Pathology [25]. These recommendations were based on the following susceptibility data for the geographic region: S. pneumoniae was highly susceptible to moxioxacin (99.6%), levooxacin (99.6%), telithromycin (98.92%), and high-dose amoxicillin

(94.9%). However, high resistance rates for cefaclor (41.6%), cefuroxime and cefpodoxime (each 31.4%), and the macrolides (35%) were observed. In Spain, H. inuenzae was usually susceptible to moxioxacin (100%), levooxacin (100%), amoxicillin-clavulanate (99.5%), cefuroxime (99.3%), and cexime (99.8%). Approximately 25% of H. inuenzae strains were blactamase positive. For immunocompetent patients with mild maxillary disease and no comorbidity, either no treatment or amoxicillin is recommended. For patients with moderate infection, including patients who have underlying immunosuppression, comorbidities, or frontal/sphenoid disease, a respiratory uoroquinolone is the rst-line choice. Third-generation cephalosporins are advised for patients with severe complicated episodes. FLUOROQUINOLONES IN ABRS The respiratory uoroquinolones have excellent activity against H. inuenzae and M. catarrhalis, as well as potency against S. pneumoniae. Although there remain some questions about the proper role of uoroquinolones in the treatment of ABRS, uoroquinolones appear to be highly effective as second-line therapy or as rst-line therapy for certain sicker patients. The SAHPs 2004 recommendations on uoroquinolone use state that uoroquinolones should not be used indiscriminately, and the most pharmacodynamically potent uoroquinolones should be used to treat the suspected pathogen. When the decision is made to use a uoroquinolone, preference should be given to agents that are most likely to achieve optimal pharmacokinetic/pharmacodynamic parameters [5, page 29]. S. pneumoniae pharmacodynamics. Because of increasing
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Table 1. Treatment guidelines for adults with acute bacterial rhinosinusitis.

No recent antimicrobial use (past 46 weeks) Amoxicillin (1.54 g/day) Cefpodoxime proxetil Cefuroxime axetil Cefdinir d Respiratory uoroquinolone Amoxicillin-clavulanate (4 g/250 mg)c Ceftriaxone e Combination therapy History of b-lactam hypersensitivity TMP-SMZ

Amoxicillin-clavulanate (1.754 g/250 mg/day)

Doxcycline Macrolide (i.e., azithromycin, clarithromycin, erythromycin) Respiratory uoroquinoloned Rifampin plus clindamycin Mild or moderate diseasea With recent antimicrobial use (past 46 weeks)b Respiratory uoroquinolone Ceftriaxone Combination therapye Reevaluate patientf History of b-lactam hypersensitivity Respiratory uoroquinoloned Rifampin plus clindamycin Reevaluate patientf
NOTE. Adapted with permission from the American Academy of OtolaryngologyHead and Neck Surgery Foundation [5]. TMP-SMZ, trimethoprimsulfamethoxazole. The difference in severity of disease does not imply the presence or absence of antimicrobial resistance but indicates the relative degree of acceptance of possible therapeutic failure and the likelihood of achieving spontaneous resolution of symptoms. b Prior antibiotic therapy within 46 weeks is a risk factor for infection with resistant organisms. c The total daily dose of amoxicillin and the amoxicillin component of amoxicillin-clavulanate can vary from 1.5 to 4 g/day. Lower daily doses (1.5 g/day) are more appropriate in patients with mild disease who have no risk factors for infection with a resistant pathogen (including recent antibiotic use). Higher daily doses (4 g/day) may be advantageous in areas with a high prevalence of penicillin-resistant Streptococcus pneumoniae or drug-resistant S. pneumoniae, for patients with moderate disease, for patients who may need better coverage for Haemophilus inuenzae, or for patients with risk factors for infection with a resistant pathogen. There is a greater potential for treatment failure or resistant pathogens in these groups of patients. d Respiratory uoroquinolones include gatioxacin, levooxacin, and moxioxacin. e On the basis of the in vitro spectrum of activity; combination therapy using appropriate gram-positive and -negative coverage may be appropriate. Combination therapy regimens may include high-dose amoxicillin (4 g/day), clindamycin plus cexime (which is not currently available in the United States), high-dose amoxicillin (4 g/day), or clindamycin plus rifampin. f Reevaluation is necessary because the antibacterials recommended for initial therapy provide excellent activity against the predominant acute bacterial rhinosinusitis pathogens, including S. pneumoniae and H. inuenzae. Additional history, physical examination, cultures, and/or CT scan may be indicated, and the possibility of other less common pathogens considered.
a

d c

Amoxicillin-clavulanate (4 g/250 mg)

demands to promote more-sensible antimicrobial use, the most potent antimicrobial therapy must be carefully selected to target the suspected pathogens and to minimize the emergence of resistant mutants. Among the pathogens most commonly associated with ABRS, S. pneumoniae is the key pathogen against which the respiratory uoroquinolones have varying potency and pharmacodynamic properties. To optimize both clinical and bacteriological success in patients with pneumococcal sinusitis episodes and to prevent the selection of resistant mutants, examination of key pharmacodynamic measures (Cmax : MIC or area under the plasma concentration timecurve [AUC]:MIC values), including concentrations to prevent the selection of resistant mutants, needs to be considered. When commonly reported MIC90 values against S. pneumoniae and steady-state AUC values corrected for protein binding are used, the AUC:MIC values for the 3 respiratory uoroquinolones are as follows: 200 for moxioxacin (400 mg/day), 166 for gatioxacin (400 mg/day), 71 for levooxacin (750 mg/ day), and 34 for levooxacin (500 mg/day) [2629]. On the basis of the premise that the AUC:MIC must exceed 3040 for S. pneumoniae to achieve desired patient success, only moxioxacin, gatioxacin, and high-dose levooxacin consistently exceed the suggested minimum ratio. The importance of pharmacodynamics is not limited to serum concentrations but should be evaluated for targeted tissue sites. Two studies have shown that moxioxacin achieves high concentrations in sinus tissues [30]. Following the administration of single oral doses (400 mg) to 20 patients, Dinis et al. [30] found that moxioxacin was distributed extensively throughout both inamed and noninamed sinus mucsoa, although concentrations were highest in the maxillary sinus. The tissue-to-blood ratios were 14:1 at most sites. In a second study, Gehanno et al. [31] measured moxioxacin concentrations in sinus tissue after steady-state conditions (i.e., 400 mg/day for 5 days) had been reached in patients with chronic sinusitis. Concentrations of moxioxacin in sinus mucosa were consistently higher than those in plasma: 4.565.73 mg/kg at 26 h after administration of a dose versus 1.252.81 mg/kg at 12 36 h after administration of a dose. The tissue:plasma ratio was 200%328.9% (236 h after administration of a dose). Similar ndings were found in other types of sinus tissue (e.g., maxillary sinus and anterior ethmoid sinus or nasal polyps). In both studies, sinus mucosal concentrations were well above MIC90 values of moxioxacin against a wide range of bacteria. In a study that used pharmacodynamic end points to evaluate gatioxacin for the treatment of acute maxillary sinusitis, the median 24-h AUC for sinus aspirates and plasma samples was 1.51 (range, 0.882.23) [32]. The emergence of resistance to uoroquinolones in S. pneumoniae occurs after mutations in the genes encoding the target topoisomerase enzymes (i.e., parC, which encodes the A sub-

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unit of DNA topoisomerase IV, and gyrA, which encodes the A subunit of DNA gyrase) [33]. Resistance to this pathogen occurs in 2 discrete steps, with spontaneous mutations occurring initially in parC and secondarily in gyrA [3436]. Because there is increasing evidence that selection of resistant pneumococcal strains may vary among the respiratory uoroquinolones, a new pharmacodynamic toolthe mutant prevention concentration (MPC) theoryhas been developed. In brief, the MPC is the concentration required to inhibit the growth of the least susceptible wild-type mutants (i.e., single-step mutants), whereas the MIC is the lowest concentration needed to stop growth of wild-type bacteria [37]. Among a large number of clinical isolates of uoroquinolone-susceptible S. pneumoniae (n p 146), moxioxacin was found to be the uoroquinolone least likely to select for resistant mutants, followed by gatioxacin and levooxacin [38, 39]. Additional preliminary in vitro data suggest that AUC:MICs 1100 may protect against the selection of resistant S. pneumoniae mutants [40]. Moxioxacin clinical trials. Burke et al. [41] reported the rst ndings of the efcacy of moxioxacin for the treatment of 542 adult patients with community-acquired ABRS (i.e., radiographic evidence plus baseline signs and symptoms present for 17 days but !4 weeks). After a 10-day oral regimen of either moxioxacin (400 mg/day) or cefuroxime axetil (250 mg b.i.d.), the percentage of patients with a clinical response at the end of therapy (714 days after therapy) was 90% and 89%, respectively. Clinical relapse rates were low for both treatment groups (3 patients receiving moxioxacin and 5 patients receiving cefuroxime axetil). Siegert et al. [42] conducted a multicenter trial in which 242 patients were randomized to receive 400 mg of moxioxacin once daily for 7 days and were compared with 251 patients who received 250 mg of cefuroxime axetil twice daily for 10 days. The clinical success rate at the end of treatment was signicantly higher in moxioxacin-treated patients (96.7% [204/211]) than in the cefuroxime axetiltreated patients (90.7% [204/225]; 95% CI, 1.5%10.6%). At baseline, a total of 224 isolates (45%; 109 from moxioxacin-treated patients and 115 from cefuroxime axetiltreated patients) were obtained by use of middle meatal swabs or cannula and were evaluated for efcacy. The response rates of the major respiratory pathogens to treatment with moxioxacin or cefuroxime axetil were as follows: for S. pneumoniae, 97.4% for moxioxacin and 93.8% for cefuroxime axetil; for H. inuenzae, 96.6% for moxioxacin and 85.7% for cefuroxime axetil; and for M. catarrhalis, 100% for moxioxacin and 88.9% for cefuroxime axetil. Rakkar et al. [43] also established that moxioxacin (400 mg/day) was at least as effective as amoxicillin-clavulanate (875 mg b.i.d.); clinical resolution at the test-of-cure visit (i.e., 14 21 days after therapy) was reported for 85% versus 82% of patients whose results could be evaluated for efcacy, respec-

tively. Gehanno et al. [44] enrolled 258 patients in a prospective study to evaluate the use of oral moxioxacin (400 mg/day for 7 days) for treatment of acute maxillary sinusitis after rst-line treatment failure, as well as in patients with a high risk of complications. Positive plain-lm radiographs were used as part of the enrollment criteria. Ninety-two patients had 102 bacterial isolates identied via middle meatus cultures, of which 29% were S. pneumoniae and 27% were H. inuenzae. The rate of resistance to penicillin for S. pneumoniae in this series was 65%, and 58% of H. inuenzae isolates were b-lactamase positive. Of 216 efcacy-valid patients, the clinical and bacteriological success rates 710 days after treatment were 92.6% and 96%, respectively. Klossek et al. [45] compared the efcacy of oral moxioxacin (400 mg/day for 7 days) with that of oral trovaoxacin (200 mg/ day for 10 days) in 452 patients with radiologically proven ABRS. At the evaluation performed 710 days after therapy, moxioxacin was found to be statistically equivalent to trovaoxacin (clinical success rates, 96.9% vs. 92.1%, respectively). Corresponding clinical success rates at the late follow-up visit were 94.9% and 97.6%, respectively. The most common causes of sinusitis were S. pneumoniae, H. inuenzae, and Staphylococcus aureus. Bacteriological success rates at the posttherapy evaluation were similar for both treatment groups: 94.4% for patients given moxioxacin and 90.1% for patients given trovaoxacin. In a pooled analysis of 2 clinical open-label sinusitis trials, the efcacy of moxioxacin against penicillin-susceptible and penicillin-resistant S. pneumoniae (PRSP) was examined [46]. All patients received oral moxioxacin (400 mg/day) for 710 days. Of 806 patients enrolled in the 2 studies, 69 patients had ABRS caused by S. pneumoniae, including 15 conrmed cases of PRSP infection. Approximately one-third of episodes (26 [37.7%]) were considered to be severe, according to the investigators evaluation. Clinical and bacteriological success at the test-of-cure visit (2137 days after completion of therapy) occurred in 93.3% (14/15) of patients with PRSP infection, compared with 88.4% (61/69) of all patients infected with S. pneumoniae, regardless of penicillin susceptibility. Moxioxacin had low MIC values (0.060.25 mg/L) against all 15 PRSP strains. The results for this small cohort of patients with ABRS caused by PRSP demonstrate the effectiveness of moxioxacin. Gatioxacin clinical trials. In a large noncomparative study, the efcacy of gatioxacin (400 mg/day for 10 days) was evaluated in 111,000 adult patients with ABRS [47]. The primary pretherapy pathogens isolated were M. catarrhalis (91% of which were b-lactamase producers), H. inuenzae (28% of which were b-lactamase producers), S. pneumoniae (32% of which were penicillin resistant), and S. aureus. Among 10,353 patients who could be clinically evaluated, 91.6% experienced a cure, and 190% of major pathogens were eradicated. A second study by Sher et al. [48] evaluated the efcacy of
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a short-course, 5-day gatioxacin regimen (400 mg/day), compared with standard 10-day regimens with either amoxicillinclavulanate (875 mg b.i.d.) or gatioxacin (400 mg/day) in 445 patients with acute, uncomplicated maxillary sinusitis. At the test-of-cure visit (714 days after therapy), clinical cure rates for patients who could be clinically evaluated were 74% for those given gatioxacin for 5 days, 80% for those given gatioxacin for 10 days, and 72% for those given amoxicillinclavulanate for 10 days. This study suggests that, for select patients with maxillary sinusitis, short-course gatioxacin therapy is effective. Levooxacin clinical trials. At least 2 comparative trials have established the effectiveness of levooxacin for the treatment of adults with ABRS [49, 50]. In one trial, a total of 535 patients who could be clinically evaluated randomly received levooxacin (500 mg/day) or amoxicillin-clavulanate (500 mg of amoxicillin t.i.d. and 125 mg of clavulanate t.i.d.) for 10 14 days [49]. Clinical cure/improvement rates, 25 days after therapy, were 88.4% for levooxacin-treated patients, compared with 87.3% for amoxicillin-clavulanatetreated patients. In a second trial, 216 patients were randomized in double-blind fashion to receive therapy with either levooxacin (500 mg/ day) or clarithromycin (500 mg b.i.d.) for 2 weeks [50]. Among 190 patients who could be evaluated, clinical cure/improvement rates were 96.0% for levooxacin, compared with 93.3% for clarithromycin. At the follow-up evaluation 1 month after therapy, 4.1% of patients receiving levooxacin and 7.2% receiving clarithromycin experienced a relapse of symptoms. Although these studies demonstrate the effectiveness of levooxacin for ABRS, both of these studies were conducted almost 10 years ago, prior to the emergence of multidrug resistance in S. pneumoniae. At the time of the writing of this article, there were no published studies evaluating the efcacy of high-dose levooxacin for the treatment of ABRS. DISCUSSION The goal of antibiotic therapy is to eradicate bacterial pathogens at the site of infection. It has been touted that the failure of an antibiotic to achieve this goal increases the potential for clinical failure, incurs further costs, and may also select bacteria that are resistant [51]. Failures are often due to infection with resistant pathogens or suboptimal pharmacokinetics/pharmacodynamics of the antimicrobial agent. Gwaltney et al. [52] recently examined a number of studies of ABRS and made the following recommendations: (1) for patients with a community-acquired bacterial sinusitis episode, antimicrobial treatment should be administered for 710 days, and (2) selected empirical agents should be effective against the most common antimicrobialresistant pathogens, including S. pneumoniae, H. inuenzae, and M. catarrhalis.
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Numerous treatment guidelines have been crafted worldwide to assist practitioners in treating patients with ABRS. Collectively, treatment guidelines from North America and some countries in Europe reveal that amoxicillin and amoxicillinclavulanate are the most commonly recommended agents for the treatment of ABRS [5, 20]. Macrolides are the second most commonly used class globally, but national guidelines from the United States, France, and Spain recommend either no role or a limited role for macrolides, because of concerns about resistance in S. pneumoniae and because of their intrinsically poor activity against H. inuenzae [5, 20]. The respiratory uoroquinolones are positioned for use in patients with moderate or severe disease and those who have a history of recent antimicrobial use, when there is a failure to improve on the results of initial therapy after 72 h, and if there is an environment of antimicrobial resistance [5]. The increase in rates of antimicrobial resistance in S. pneumoniae and H. inuenzae during the past decade has made the selection of empirical antimicrobial therapy for many respiratory tract infections, including ABRS, very challenging [53]. The role of many available oral b-lactams and macrolides in the treatment of respiratory tract pathogens is at a critical junction and requires close susceptibility monitoring, because failure rates often are as high as 25% [23]. Accordingly, the search for new agents to ll the gap continues. When the best data currently available are used, the Poole therapeutic outcomes model predicts that only the respiratory uoroquinolone or high-dose amoxicillin-clavulanate has the optimal intrinsic properties to lead to clinical success [23]. Because high-dose amoxicillin-clavulanate continues to provide high success rates (190%) for many mild episodes of ABRS, it is recommended most often as rst-line therapy in many treatment guidelines, including those from the United States [5]. Fluoroquinolones are only recommended as rst-line therapy for patients who have a recent history of failure associated with another antimicrobial, in the presence of moderate/severe disease, or if patients have received recent nonquinolone antimicrobial therapy in the prior 46 weeks [5]. The respiratory uoroquinolones have enhanced activity against penicillin-susceptible and -resistant strains of S. pneumoniae and are highly active against most strains of H. inuenzae and M. catarrhalis, including those that produce b-lactamase. Gatioxacin is twice as active against S. pneumoniae as is levooxacin, but moxioxacin is even more potent, with 8 times more activity than levooxacin [54]. Moxioxacin specically has been shown to be effective for the treatment of ABRS due to PRSP strains [46]. All 3 respiratory uoroquinolones have been shown to be effective for the treatment of patients with ABRS, in clinical trials conducted during the past decade. Although uoroquinolones are gaining a larger role in the treatment of ABRS, clinicians must use uoroquinolones

judiciously and appropriately to maintain the activity of the class [55]. Although it is not evident from the outcomes of clinical trials, there are some subtle and important pharmacodynamic differences among the 3 widely used respiratory uoroquinolones. The most evident difference is the pharmacodynamic activity in S. pneumoniae, wherein gatioxacin and moxioxacin have a predictably higher serum AUC:MIC (1135) than does levooxacin, which may discourage the selection of resistant mutants [40]. In addition to having 24-h free drug AUC:MIC values, it appears that, if concentrations in sinus tissues exceed the MPC, selection of resistance strains should be minimal [35, 36, 38, 39, 55]. At present, respiratory uoroquinolones are recommended as second-line therapy for the management of mild episodes of ABRS in patients who have no history of recent antimicrobial use and as rst-line therapy for patients who recently have received antibiotics or who have moderate disease and are allergic to b-lactams [5]. Efforts to minimize inappropriate prescribing of uoroquinolone therapy for ABRS are important to maintain the integrity of t his class of compounds. Selection of the most potent uoroquinolone (i.e., one that demonstrates optimal microbiological and pharmacodynamic properties) is of utmost importance to increase the likelihood of clinical success while discouraging the emergence of resistance.
Acknowledgments
Financial support. This paper was generated from a symposium, Moxioxacin: An Assessment after 4 Years of Clinical Use (1618 April 2004; Naples, FL), through an unrestricted educational grant from Bayer Pharmaceuticals (West Haven, CT). Potential conicts of interest. J.B.A.: speakers bureau of GlaxoSmithKline, Bayer Pharmaceuticals, and Abbott.

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