Otolaryngology–Head and Neck Surgery (2006) 134, 10-17

ORIGINAL RESEARCH

A Trial of High-Dose, Short-Course Levofloxacin

for the Treatment of Acute Bacterial Sinusitis

Michael Poole, MD, PhD, Jack Anon, MD, Margaret Paglia, MHSA, BSN,Jim Xiang, PhD, Mohammed Khashab, MBA, and James Kahn, MD,

Savannah, Georgia; Pittsburgh, Pennsylvania; and Raritan, New Jersey

OBJECTIVE: Compare two dosage strengths of levofloxacin inthe treatment of acute bacterial sinusitis.STUDY DESIGN AND SETTING: Multicenter clinical trialcomparing levofloxacin 750 mg for 5 days vs levofloxacin 500 mgfor 10 days.RESULTS: Sinus fluid samples were obtained by antral punc-ture (59.2%) or by sinus endoscopy (40.8%). Among microbio-logically evaluable patients, 91.4% (139/152) of patients receivinglevofloxacin 750 mg achieved clinical success vs 88.6% (132/149)of patients receiving levofloxacin 500 mg (95% CI �10.0, 4.2).Clinical success rates by pathogen were above 90% in both treat-ment groups for the 3 typical pathogens of acute sinusitis: Strep-tococcus pneumoniae, Haemophilus influenzae, and Moraxella ca-tarrhalis. The safety profile of the 2 dosage strengths was similar.CONCLUSION: Levofloxacin 750 mg for 5 days is noninferiorto levofloxacin 500 mg for 10 days.SIGNIFICANCE: Levofloxacin 750 mg for 5 days represents asafe and effective treatment regimen for acute bacterial sinusitis.EBM rating: A-1b© 2006 American Academy of Otolaryngology–Head and NeckSurgery Foundation, Inc. All rights reserved.

Among adult otolaryngology patients seeking care forsymptoms of sinusitis, 50% to 80% may have acute

bacterial sinusitis (ABS).1 In the absence of effective antibiotictherapy, ABS is associated with serious and potentially life-threatening complications, including cavernous sinus thrombo-sis, meningitis, orbital cellulitis or abscess, and brain abscess.2

From the Georgia Ear Institute (Dr Poole), the University of Pittsburgh(Dr Anon), and Ortho-McNeil Pharmaceutical, Raritan (Ms Paglia, Dr Xiang,Mr Khashab, and Dr Kahn).

This study was sponsored by Ortho-McNeil Pharmaceutical.

These data have been presented in poster form at the 2005 Annual

0194-5998/$32.00 © 2006 American Academy of Otolaryngology–Head and Necdoi:10.1016/j.otohns.2005.11.026

Effective antibiotic therapy has been shown to eradicate orsubstantially reduce bacterial load in the sinus cavity, decreasethe rate of complications, and prevent progression to chronicsinusitis. The major pathogens in ABS are Streptococcus pneu-moniae, Haemophilus influenzae, and Moraxella catarrhalis.Other causative organisms include Staphylococcus aureus,other streptococcal species, and anaerobic bacteria.2,3

While microbiologic testing of fluid obtained by sinuspuncture is the most widely accepted reference standard fordiagnosis, its routine use is not feasible due to patient reluc-tance to consent to the procedure due to perceived or realdiscomfort.4 The utility of an alternative sampling method,rigid sinonasal endoscopy, has been confirmed in recent stud-ies.5,6,7 In practice, the diagnosis of acute bacterial sinusitis isbased on clinical evaluation and radiologic imaging, and anti-microbial therapy is initiated empirically. Levofloxacin (LE-VAQUIN, Ortho-McNeil Pharmaceutical, Raritan, NJ) hasbeen previously studied and approved for use at a dose of 500mg daily for 10 to 14 days for the treatment of ABS due to S.pneumoniae, H. influenzae, and M. catarrhalis. The 750-mgdosage form of levofloxacin, the pharmacodynamics of whichallow for a shorter course of therapy, has been previouslystudied in other respiratory infections including bronchitis andcommunity-acquired pneumonia. In this study, we comparedthe efficacy and safety of a 5-day course of levofloxacin at adose of 750 mg per day with that of levofloxacin 500 mg perday for 10 days in the treatment of acute bacterial sinusitis.

Meeting of the American Academy of Allergy, Asthma, and Immunology,San Antonio, TX, March 18-22, 2005.

Reprint requests: James Kahn, MD, Ortho-McNeil Pharmaceutical,1000 Route 202, Raritan, NJ 08869.

E-mail address: jkahn@ompus.jnj.com.

k Surgery Foundation, Inc. All rights reserved.

11Poole et al A Trial of High-Dose, Short-Course Levofloxacin . . .

METHODS

Study DesignThis was a multicenter, randomized, double-blind, active treat-ment–controlled, noninferiority study of adult outpatients withacute bacterial sinusitis conducted at 58 sites in the UnitedStates. Participating institutions’ Institutional Review Boardsapproved the protocol and written informed consent was ob-tained before initiation of study procedures. All patients had toconsent to maxillary antral puncture (MAP) or endoscopicsinus sampling at study entry.

Study PopulationPersons age �18 years with a clinical diagnosis of ABSbased on clinical signs and symptoms and radiographicevidence were eligible for enrollment. Because this trialfocused on patients with microbiologically documentedABS, no minimum duration of symptoms was required;however, patients were required to have fewer than 28 daysof symptoms. Patients had to have at least one of thefollowing: purulent nasal or postnasal drainage; facial pain,tenderness, pressure, or tightness over the maxillary sinusesor periorbital region; nasal or sinus congestion; and/or max-illary tooth pain. Patients were also required to have visiblenasal purulence on physical or endoscopic examination.Radiologic exam (CT scan or sinus x-rays [multiple views])had to be performed within 48 hours of study entry andshow total sinus opacification or an air fluid level. Patientscould not have had more than 2 other episodes of bacterialsinusitis within the previous 12 months. Patients withchronic sinusitis (defined as current symptoms for morethan 4 weeks or more than 2 episodes of ABS within theprevious 12 months) were excluded, as were patients withprevious head or neck surgery and/or a history of seriouscomplications of sinusitis (eg, brain abscess or venousthrombosis). Patients who could not take oral therapy, whorequired hospitalization and/or surgery for their sinusitis,who were immunosuppressed, or who had cystic fibrosiswere excluded. Hospitalization lasting 48 hours or more forany cause within 2 weeks prior to study entry, or within themonth prior to study entry and during which antimicrobialtherapy was administered, were also criteria for exclusion.Patients who had received previous systemic antimicrobialtherapy within 72 hours of study entry were excluded with theexception of those who had received �24 hours of therapy andthose who had failed a minimum of 72 hours of antimicrobialtherapy with an agent other than levofloxacin or any othermember of the quinolone class of antimicrobials.

Study ProceduresAll subjects underwent either MAP or endoscopicallyguided collection at study entry. For patients in whom anendoscopic specimen was obtained, visualization of theappropriate anatomical landmarks was required and the fol-lowing potential findings were to be addressed: description ofamount and character of secretions, confirmation of the nature

of the sample collected for culture as being appropriate, pres-

ence of hyperemia, and any anatomical abnormalities. Patientswere randomized according to a computer-generated random-ization schedule to receive levofloxacin 750 mg daily bymouth for 5 days followed by 5 days of matched placebo orlevofloxacin 500 mg daily by mouth for 10 days. Patientswere evaluated at study entry, at an on-therapy visit (day3-5), at a test-of-cure visit (day 17-22), and at a poststudyvisit (day 35-45). Clinical response was evaluated at thetest-of-cure and poststudy visits. During the period betweenstudy entry and the test-of-cure visit, patients were allowedto use only acetaminophen as an analgesic and only pseudo-ephedrine as a decongestant. The use of nasal steroids wasprohibited.

MicrobiologySamples obtained by MAP or endoscopic sampling weresent for Gram stain and culture and susceptibility testing.Acceptable sinus specimens were required to be collectedwithin 24 hours after study entry and to contain �25 poly-morphonuclear leukocytes and �10 squamous epithelial cellsper low-powered field. For organisms obtained through endo-scopically guided collection and MAP, semiquantitativegrowth of �1 � (�101-102 colony-forming units [CFU]/mL)was required, except for S. aureus, which was required to havea semiquantitative growth �2 � (�102-103 CFU/mL) to beconsidered an acceptable specimen.

Clinical and Microbiologic EfficacyThe primary analysis population (microbiologically evalu-able) consisted of patients with microbiologically confirmeddiagnoses who were compliant with the study protocol.Clinical response was defined as cure, improvement, failure,or unable to evaluate. Cure was defined as resolution ofpretreatment abnormal clinical signs and symptoms with nofurther antimicrobial therapy required for the infection. Im-provement was defined as clinical findings subsiding sig-nificantly but with incomplete resolution of clinical evi-dence of infection in a patient who required no furtherantimicrobial therapy for sinusitis. Clinical failure was de-fined as no apparent response to therapy or an incompleteresponse requiring additional antimicrobial therapy for si-nusitis. Microbiologic response was defined as eradicated,presumed eradicated, persisted, presumed persisted, or un-known. In the absence of a posttherapy visit culture, aresponse of “presumed eradicated” was used to classify themicrobiologic outcome for patients deemed clinical suc-cesses, and the term “presumed persisted” was used toclassify the microbiologic outcome for patients deemed tohave had clinical failure.

Statistical AnalysesThe prospectively defined primary efficacy endpoint in thisstudy was the clinical success rate (proportion of patientswho were cured or improved) in the microbiologicallyevaluable population at study day 17-24. For the purpose of

the statistical analysis, the test-of-cure window was ex-

12 Otolaryngology–Head and Neck Surgery, Vol 134, No 1, January 2006

panded by 2 days to broaden the inclusion of subjects forevaluation. The secondary efficacy variables included: mi-crobiologic response at the test-of-cure visit; microbiologicresponse by admission pathogen at the test-of-cure visit; andclinical and microbiologic responses of patients at poststudywho completed therapy and were evaluated as having clin-ical success at the test-of-cure visit. A two-sided 95% con-fidence interval (CI) around the difference between treatmentgroups (levofloxacin 500 mg regimen minus levofloxacin 750mg regimen) was computed.8 To conclude that a 5-daycourse of levofloxacin 750 mg daily was at least as effica-cious as a 10-day course of levofloxacin 500 mg daily, theupper bound of the 95% CI had to be less than 15%.Descriptive statistics were used to summarize treatment-emer-gent adverse events and pretherapy to posttherapy changes inlaboratory test results and vital signs. Two-sided 95% CIs werecalculated for the differences between the treatment groups inthe rates of treatment-emergent adverse events overall andwithin each body system, and for the most commonly occur-ring treatment-emergent adverse events.

RESULTS

Patient populations in the 2 treatment groups were compa-

Table 1

Demographics (intent-to-treat population)

Levofloxacin 750(N � 389)

n (%)

SexMale 152 (39.1)Female 237 (60.9)

RaceCaucasian 291 (74.8)Black 60 (15.4)Asian 5 (1.3)Hispanic 25 (6.4)Other 8 (2.1)

Age�45 245 (63.0)46-64 123 (31.6)�65 21 (5.4)

Smoking historyNonsmoker 231 (59.4)Current smoker 84 (21.6)Ex-smoker 74 (19.0)

Pack yearsN 150Mean � SD 17.1 � 18.85

Allergy historyYes 185 (47.6)No 204 (52.4)

ProcedureMAP 230 (59.1)Endoscopy 159 (40.9)

rable. In both arms, women were more commonly entered

than were men. The majority of patients were 45 years ofage or younger and were nonsmokers. Roughly 50% ofpatients entered had a history of allergies. Among patientsin the microbiologically evaluable population, the meanduration of symptoms was 10.3 days for patients treated withlevofloxacin 750 mg daily and 11.7 days for patients treatedwith levofloxacin 500 mg daily with a minimum duration ofsymptoms of 2 days and 1 day, respectively. Although patientswith a history of head and neck surgery were to be excluded,7 patients with prior sinus surgery were included in the micro-biologically evaluable population. Approximately 60% of pa-tients had their sinus fluid sample obtained by antral punctureand 40% by endoscopy (Table 1).

A total of 784 patients were randomized, of which 780patients took at least 1 dose of study medication and wereincluded in the intent-to-treat population. Three hundredeighty-nine patients received levofloxacin 750 mg daily for5 days and 391 patients received levofloxacin 500 mg for 10days. Three hundred and seventy-two and 373 patients,respectively, completed therapy in each arm (Table 2). Themost common reason for premature discontinuation in bothtreatment arms was adverse events, whether drug-related ornot, which led to discontinuation of 10 (2.6%) patients inthe 750-mg group and 8 (2.0%) patients in the 500-mg

Levofloxacin 500(N � 391)

Overall(N � 301)

n (%) n (%)

173 (44.2) 325 (41.7)218 (55.8) 455 (58.3)

299 (76.5) 590 (75.6)62 (15.9) 122 (15.6)2 (0.5) 7 (0.9)

25 (6.4) 50 (6.4)3 (0.8) 11 (1.4)

242 (61.9) 487 (62.4)112 (28.6) 235 (30.1)37 (9.5) 58 (7.4)

247 (63.2) 478 (61.3)71 (18.2) 155 (19.9)73 (18.7) 147 (18.8)

137 28716.1 � 18.86 16.6 � 18.83

219 (56.0) 404 (51.8)172 (44.0) 376 (48.2)

232 (59.3) 462 (59.2)159 (40.7) 318 (40.8)

group (Table 2).

or im

13Poole et al A Trial of High-Dose, Short-Course Levofloxacin . . .

Among microbiologically evaluable patients at the test-of-cure visit, clinical success occurred among 91.4% (139/152) of patients treated with levofloxacin 750 mg daily for5 days. In patients treated with 500 mg levofloxacin for 10days, clinical success occurred in 88.6% (132/149) (95%CI �10.0, 4.2), thereby satisfying the protocol-specifiedcriterion of noninferiority for the 750-mg regimen. Fail-ure occurred in 8.6% (13/152) and 11.4% (17/149) ofeach group, respectively (Table 3). Among patients re-ceiving levofloxacin 750 mg assessed as having achievedclinical success, 44.7% (68/152) were cured and 46.7%(71/152) were improved. Among patients receiving levo-floxacin 500 mg, 53.0% (79/149) were cured and 35.6%(53/149) were improved. For patients receiving levo-floxacin 750 mg, results were similar regardless of sinusfluid sampling method. However, among patients receivinglevofloxacin 500 mg, patients whose sinus fluid was sam-pled by antral puncture had a better outcome than those whounderwent endoscopy (Table 4).

Clinical response against the common pathogens as-sociated with sinusitis (S. pneumoniae, H. influenzae, andM. catarrhalis) was high (�90% for all 3 pathogens) inboth groups. Approximately 75% of patients infectedwith S. aureus in both treatment groups were either curedor improved (Table 5). Microbiologic response by patho-gen at test-of-cure was above 90% in both arms for thecommon pathogens associated with acute sinusitis.Though not statistically significant, the eradication ratefor S. aureus was higher among patients treated withlevofloxacin 500 mg than among patients treated with

Table 2

Study completion/withdrawal information (intent-to-tr

Subject disposition

Total completing study medicationTotal unknown for discontinuation from study medicatTotal who withdrew from study before test-of-cure visiTotal who discontinued study medication

Reason for discontinuation from study medicationSubject choiceLost to follow-upAdverse eventClinical failureMajor protocol violationResistant pathogenb

OtherTotal who withdrew from study between last dose and

test-of-cure visitTotal who completed study through test-of-cure visitTotal eligible for poststudy visit evaluationc

Completed poststudy visitaPercentages based on total number of subjects with continuabSuspected, confirmed, or reported resistant pathogen (assoccIncludes all subjects who completed therapy and were cured

levofloxacin 750 mg (83.3% [10/12] vs 76.0% [19/25],

respectively) (Table 6). Overall susceptibility to levo-floxacin among all pathogens isolated was 98.9% (350/354).

Long-term clinical success and microbiologic eradica-tion outcomes at poststudy were similar between the 2treatment groups. Among patients who were treated withlevofloxacin 750 mg, 94.1% (127/135) were classified ashaving long-term clinical cure or improvement vs 93.1%(121/130) of patients receiving levofloxacin 500 mg.With regard to microbiologic eradication, 94.1% (127/135) of patients treated with levofloxacin 750 mg wereclassified as having long-term eradication/presumederadication while 94.6% (123/130) receiving levofloxacin500 mg were so classified (Table 7). Two patients in the500-mg treatment arm were deemed clinical failures butdemonstrated continued eradication of the admissionpathogen through the poststudy visit based on repeatsampling. Long-term clinical relapse rates were also sim-ilar between the 2 treatment groups (5.9% (8/127) vs6.9% (9/123), respectively).

Among patients who took at least 1 dose of studymedication and provided on-therapy safety information(safety-evaluable population), the safety profile of the 2dosage strengths was similar. Overall, 39.8% (155/389)of patients receiving levofloxacin 750 mg and 34.5%(135/391) of patients receiving levofloxacin 500 mg ex-perienced an adverse event. Incidence of treatment-emer-gent adverse events (occurring during treatment or up tostudy day 24) reported by �2.0% of patients by body

opulation)

Levofloxacin 750 mg(N � 389)

n (%)a

Levofloxacin 500 mg(N � 391)

n (%)a

372 (95.6) 373 (95.4)2 (0.5) 1 (0.3)

22 (5.7) 22 (5.6)15 (3.9) 17 (4.3)

0 (0.0) 1 (0.3)0 (0.0) 0 (0.0)

10 (2.6) 8 (2.0)1 (0.3) 4 (1.0)3 (0.8) 1 (0.3)0 (0.0) 0 (0.0)1 (0.3) 3 (0.8)

7 (1.8) 5 (1.3)365 (93.8) 368 (94.1)333 (85.6) 346 (88.5)322 (82.8) 339 (86.7)

ithdrawal information.ith evidence of ineffective treatment).

proved at the test-of-cure visit.

eat p

iont

tion/wiated w

system was also similar between the 2 groups (Table 8).

l succe

14 Otolaryngology–Head and Neck Surgery, Vol 134, No 1, January 2006

DISCUSSION

This analysis focused on efficacy in patients with microbio-logically documented ABS rather than all patients entered(intent-to-treat population). The 500-mg dosage regimen hadbeen previously approved for use in treating this infection.Clinical success was similar in the 2 treatment groups, indi-cating that the higher dose of levofloxacin administered for ashorter period is as effective as the lower dose administered for

Table 3

Clinical success/nonsuccess at test-of-cure by sample

(microbiologically evaluable population)

Levofloxacin 750

Sample collection methodSuccessa

n/N (%)Nons

n/N

MAP 81/90 (90.0) 9/9Enterobacter aerogenes 1/1 (100.0) 0/Haemophilus influenzae 19/21 (90.5) 2/2Haemophilus parainfluenzae 9/9 (100.0) 0/Moraxella catarrhalis 10/11 (90.9) 1/1Proteus mirabilis 0 (0.0)Pseudomonas aeruginosa 2/3 (66.7) 1/Staphylococcus aureus 9/12 (75.0) 3/1Streptococcus pneumoniae 25/27 (92.6) 2/2Streptococcus pyogenes 3/3 (100.0) 0/

Endoscopy 58/62 (93.5) 4/6Enterobacter aerogenes 4/4 (100.0) 0/Haemophilus influenzae 16/16 (100.0) 0/1Haemophilus parainfluenzae 1/1 (100.0) 0/Moraxella catarrhalis 6/6 (100.0) 0/Proteus mirabilis 2/2 (100.0) 0/Pseudomonas aeruginosa 3/4 (75.0) 1/Staphylococcus aureus 10/13 (76.9) 3/1Streptococcus pneumoniae 17/18 (94.4) 1/1Streptococcus pyogenes 2/2 (100.0) 0/

Total 139/152 (91.4) 13/15

Note: N for pathogen of primary interest is the number ofpathogens at study entry.aSuccess rates include the clinical response categories of curebNonsuccess rates include the clinical response category of facDifference in success rates (levofloxacin 500 mg minus levofldTwo-sided 95% confidence intervals (with continuity correlevofloxacin 750 mg daily by mouth 5-day regimen) in clinica

Table 4

Clinical outcomes at test-of-cure (microbiologically eva

Sample collectionmethod

Levofloxacin 750

Curedn/N (%)

Improvedn/N (%)

MAP 41/90 (45.6) 40/90 (44.4) 9Endo 27/62 (43.5) 31/62 (50.0) 4Total 68/152 (44.7) 71/152 (46.7) 13/

a longer period. Adverse events were also similar between the2 treatment groups, as has been observed in previous studiescomparing the 2 dosages.

There are several potential advantages associated with high-dose, short-course therapy with fluoroquinolone antimicrobialssuch as levofloxacin. The kill rates of these agents are concen-tration dependent. Because of this, therapeutic outcome islinked to area under the concentration curve (AUC) rather thanto time above the minimum inhibitory concentration (MIC).9

tion method and pathogen of primary interest

Levofloxacin 500 mg

sb Successn/N (%)

Nonsuccessn/N (%) Differencec (95% CI)d

0) 89/95 (93.7) 6/95 (6.3) 3.7 (�4.8, 12.1)) 1/2 (50.0) 1/2 (50.0)) 25/27 (92.6) 2/27 (7.4)) 10/11 (90.9) 1/11 (9.1)) 13/13 (100.0) 0/13 (0.0)) 2/2 (100.0) 0 (0.0)3) 5/7 (71.4) 2/7 (28.6)0) 3/3 (100.0) 0/3 (0.0)) 26/27 (96.3) 1/27 (3.7)) 2/2 (100.0) 0 (0.0)

) 43/54 (79.6) 11/54 (20.4) �13.9 (�27.2, �0.6)) 1/2 (50.0) 1/2 (50.0)) 13/14 (92.9) 1/14 (7.1)) 1/1 (100.0) 0/1 (0.0)) 5/6 (83.3) 1/6 (16.7)) 2/3 (66.7) 1/3 (33.3)0) 2/2 (100.0) 0 (0.0)1) 6/9 (66.7) 3/9 (33.3)) 14/17 (82.4) 3/17 (17.6)) 3/3 (100.0) 0/3 (0.0)

) 132/149 (88.6) 17/149 (11.4) �2.9 (�10.0, 4.2)

ts who had the pathogen alone or in combination with other

improved.

750 mg).were calculated around the difference (comparator minusss rates (cured and improved).

e population)

Levofloxacin 500

re)

Curedn/N (%)

Improvedn/N (%)

Failuren/N (%)

0.0) 53/95 (55.8) 36/95 (37.9) 6/95 (6.3).5) 26/54 (48.1) 17/54 (31.5) 11/54 (20.4).6) 79/149 (53.0) 53/149 (35.6) 17/149 (11.4)

collec

mg

ucces(%)

0 (10.1 (0.01 (9.59 (0.01 (9.10 (0.03 (33.2 (25.7 (7.43 (0.0

2 (6.54 (0.06 (0.01 (0.06 (0.02 (0.04 (25.3 (23.8 (5.62 (0.0

2 (8.6

subjec

d andilure.oxacinction)

luabl

Failun/N (%

/90 (1/62 (6152 (8

ombin

15Poole et al A Trial of High-Dose, Short-Course Levofloxacin . . .

Higher doses may result in more rapid resolution of symptomsand shorter-course therapy may improve patient complianceand decrease the incidence of adverse events. The most com-pelling reason, however, is reducing exposure to the drug inorder to help prevent the development of resistance. High peakconcentration has been linked to prevention of the emergenceof resistance.10,11 Shorter-course regimens also have implica-tions for preventing the emergence of resistance. It is nowgenerally accepted that the development of resistance is mostclosely associated with the amount of drug to which the patientis exposed.10 Shorter-course therapies reduce total drug expo-sure over the course of treatment.

In this study, we utilized both MAP and endoscopy astechniques for sampling sinus fluid. Previous studies, inwhich samples for microbiologic evaluation have been

Table 5

Clinical response rates at test-of-cure visit by pathoge

population)

Levofloxac

Pathogen of interesta NbCuredn (%)

Impn

Enterobacter aerogenes 5 2 (40.0) 3 (Haemophilus influenzae 37 21 (56.8) 14 (Haemophilus parainfluenzae 10 4 (40.0) 6 (Moraxella catarrhalis 17 7 (41.2) 9 (Proteus mirabilis 2 1 (50.0) 1 (Pseudomonas aeruginosa 7 4 (57.1) 1 (Staphylococcus aureus 25 10 (40.0) 9 (Streptococcus pneumoniae 45 20 (44.4) 22 (Streptococcus pyogenes 5 2 (40.0) 3 (

Note: Percentages are percentages of N for the pathogen aaN � 5 in either treatment group.bN � number of patients who had the pathogen alone or in c

Table 6

Microbiologic eradication at test-of-cure by pathogen

Pathogen of interesta

Levofloxacin 75

Eradicatedb

n/N (%)

Enterobacter aerogenes 5/5 (100)Haemophilus influenzae 35/37 (94.6)Haemophilus parainfluenzae 10/10 (100.0)Moraxella catarrhalis 16/17 (94.1)Proteus mirabilis 2/2 (100.0)Pseudomonas aeruginosa 5/7 (71.4)Staphylococcus aureus 19/25 (76.0)Streptococcus pneumoniae 43/45 (95.6)Streptococcus pyogenes 5/5 (100.0)aN � 5 in either treatment group.bEradicated includes presumed eradicated.cDifference in eradication rates (levofloxacin 500 mg minus ledTwo-sided 95% confidence intervals (with continuity correc

pathogens identified in 10 or more patients in each treatment group

collected by both antral puncture and endoscopy, confirmthe utility of endoscopic cultures for the major pathogensinvolved in acute bacterial maxillary sinusitis. In a studyof 13 patients, endoscopically guided meatal cultureidentified the predominant bacterial pathogen and corre-lated with the cultures from maxillary sinus aspiration inover 90% of infections.5 In another study evaluating 46patients, the accuracy of endoscopy was 89.1% withrespect to recovery of the 3 major pathogens of ABS.6 Anadditional study of 24 patients in a single center demon-strated an accuracy of 88.5% for endoscopy. 7 Further,prospective studies with a larger sample size have beenadvocated in order to further validate the technique.4

There were some additional findings of interest amongthese data relating to sampling method. Among microbi-

rimary interesta (microbiologically evaluable

Levofloxacin 500

Failuren (%) N

Curedn (%)

Improvedn (%)

Failuren (%)

0 (0) 4 1 (25.0) 1 (25.0) 2 (50.0)2 (5.4) 41 23 (56.1) 15 (36.6) 3 (7.3)0 (0) 12 7 (58.3) 4 (33.3) 1 (8.3)1 (5.9) 19 12 (63.2) 6 (31.6) 1 (5.3)0 (0) 5 4 (80.0) 0 (0) 1 (20.0)2 (28.6) 9 3 (33.3) 4 (44.4) 2 (22.2)6 (24.0) 12 4 (33.3) 5 (41.7) 3 (25.0)3 (6.7) 44 22 (50.0) 18 (40.9) 4 (9.1)0 (0) 5 1 (20.0) 4 (80.0) 0 (0)

atment group.

ation with other pathogens at admission.

rest (microbiologically evaluable population)

Levofloxacin 500

Differencec (95% CI)dEradicated

n/N (%)

2/4 (50.0) �50.038/41 (92.7) �1.9 (�14.1, 10.2)11/12 (91.7) �8.3 (�29.0, 12.3)18/19 (94.7) 0.6 (�17.4, 18.6)

4/5 (80.0) �20.07/9 (77.8) 6.3

10/12 (83.3) 7.3 (�23.8, 38.4)40/44 (90.9) �4.6 (�16.2, 6.9)

5/5 (100.0) 0

acin 750 mg).round the difference in microbiologic eradication rates for

n of p

in 750

roved(%)

60.0)37.8)60.0)52.9)50.0)14.3)36.0)48.9)60.0)

nd tre

of inte

0

vofloxtion) a

.

visit w

16 Otolaryngology–Head and Neck Surgery, Vol 134, No 1, January 2006

ologically evaluable patients whose samples were ob-tained by endoscopy, we observed a much better clinicalsuccess rate among patients treated with levofloxacin 750mg than those treated with 500 mg. In this study, somecenters performed only antral puncture while others per-formed only endoscopy. In centers performing both pro-cedures, patients were given a choice as to which methodthey preferred to be used. No clinical criteria were usedto assign patients to antral puncture or endoscopy. Suc-cess rates for the 2 treatment groups in patients under-

Table 7

Microbiologic outcomes at poststudy (microbiologicall

Eradicated/preeradicate

n (%)

Levofloxacin 750 (N � 135)b 127 (94.1Levofloxacin 500 (N � 130) 123 (94.6

Note: All microbiologic response rates are by patient.aIncludes new infection.bIncludes only patients cured or improved at the test-of-cure

Table 8

Incidence of frequently reported (>2.0%) treatment-em

preferred term (safety-evaluable population)

Lev

Body system preferred terma

Central & peripheral nervous system disordersDizzinessHeadache

Gastrointestinal system disordersAbdominal painDiarrheaDyspepsiaMouth dryNauseac

Vomitingd

Psychiatric disordersInsomnia

Resistance mechanism disordersMoniliasis genital

Secondary termsProcedural site reactionTotal patients with adverse events

Note: Table includes treatment-emergent adverse events, ieto treatment or not.aPreferred term reported by �2.0% of patients in either treatmbTwo-sided 95% confidence interval (with continuity correctiominus levofloxacin 750 mg) in incidence of adverse events.cThe difference in drug-related nausea, ie, nausea for which threlated to treatment, was not statistically significant, occurringreceiving levofloxacin 500 mg (95% CI �1.6, 2.6).dThe difference in drug-related vomiting, ie, vomiting for wprobably related to treatment, was not statistically significant,

of patients receiving levofloxacin 500 mg (95% CI �1.7, 1.2).

going antral puncture were comparable, indicating thatdrug dosage alone was not a factor. Antral punctureremoves a much larger volume of sinus fluid than doesendoscopy and may have a therapeutic effect in and ofitself. The absence of therapeutic drainage combinedwith a lower dose of antibiotic may account for the lesssuccessful outcome in patients receiving levofloxacin 500mg who underwent endoscopy. As there were similarresults in patients receiving levofloxacin 750 mg whounderwent either antral puncture or endoscopy, it may be

luable population)

Relapsed/presumedrelapseda

n (%)Unknown

n (%)

8 (5.9) 0 (0)7 (5.4) 0 (0)

ho returned for the poststudy visit.

t adverse events summarized by body system and

cin 750 mg389)

Levofloxacin 500 mg(N � 391)

(%) n (%) 95% CIb

(3.1) 5 (1.3) (�4.0, 0.4)(4.6) 12 (3.1) (�4.4, 1.3)

(1.0) 10 (2.6) (�0.5, 3.5)(5.1) 19 (4.9) (�3.5, 2.9)(2.1) 8 (2.0) (�2.1, 2.1)(2.6) 6 (1.5) (�3.2, 1.1)(8.2) 17 (4.3) (�7.4, �0.4)(3.6) 5 (1.3) (�4.6, 0.0)

(2.8) 10 (2.6) (�2.7, 2.1)

(0.8) 10 (2.6) (�0.1, 3.7)

(1.5) 8 (2.0) (�1.5, 2.5)(39.8) 135 (34.5) (�12.2, 1.6)

that began on-therapy or up to study day 24, whether related

roup.und the difference between treatments (levofloxacin 500 mg

stigator determined that the event was definitely or probablyof patients receiving levofloxacin 750 mg vs 2.8% of patients

he investigator determined that the event was definitely oring in 1.0% of patients receiving levofloxacin 750 mg vs 0.8%

y eva

sumedd

))

ergen

ofloxa(N �

n

1218

4208

103214

11

3

6155

, those

ent gn) aro

e invein 3.3%

hich toccurr

17Poole et al A Trial of High-Dose, Short-Course Levofloxacin . . .

that the higher dose of levofloxacin overcomes the impactof not draining the sinus cavity.

We found that S. aureus continues to be a commonpathogen in community-acquired ABS. In the microbiolog-ically evaluable population in our study, roughly 12% ofpatients presented with S. aureus as the causative pathogenof their ABS. We purposely excluded patients with symp-toms for more than 28 days or with more than 2 otherepisodes of ABS within 12 months prior to study entry fromparticipation in the study. By doing so, we excluded patientswith chronic sinusitis. We also excluded patients with ahistory of previous head or neck surgery, which, in the caseof those with previous sinus surgery, might alter bacterialetiology. Patients who had been recently hospitalized werealso excluded, decreasing the chances that their infectionwas nosocomial in origin.

It is also interesting to note that the efficacy of the500-mg dosage regimen seems little changed over the lastseveral years. The original studies in ABS with the 500-mgdosage form were conducted in the mid-1990s. Two studieswere conducted, one comparative against amoxicillin/cla-vulanate and the other noncomparative. In these trials, theefficacy of levofloxacin in this infection was 88.4% and88%, respectively.12,13 These compare well with the effi-cacy of 88.6% for the 500-mg dosage regimen shown in ourstudy.

There are several potential sources of bias in this study.We studied 2 dosage levels of levofloxacin compared to oneanother. It is possible that, if we compared against anotheractive control, we would have obtained a different result.However, at least 1 previous study of the 500-mg dosagelevel was performed against an active control. We utilized 2different methodologies for the obtaining of sinus fluidsamples. Our results might have differed if we had made useof only 1 of the 2 techniques to obtain all of the samples. Wedid, however, report the outcome of the 2 sampling methodsseparately. We did not impose clinical criteria for the use ofantral puncture or endoscopy. It is possible that, if we hadimposed criteria (eg, severity criteria) for the use of one orthe other methodology, we would have obtained differentresults. While this trial followed accepted design for studyof antimicrobials in acute sinusitis, concerns over this studydesign itself have been raised. Specifically, the time pointfor the test-of-cure visit occurs relatively late in the diseasecourse. Previous data indicate that acute bacterial sinusitismay have a high rate of spontaneous resolution, leadingsome to suggest that different time points should be selectedfor evaluation of antimicrobial efficacy.14 However, thepresent study was not designed to address this issue.

In conclusion, levofloxacin 750 mg administered as a5-day treatment course was as effective as levofloxacin 500

mg administered as a 10-day treatment course. Given the

advantages inherent in a high-dose, short-course treatmentstrategy, including the diminished risk of driving resistance,we believe that levofloxacin 750 mg for 5 days is an effec-tive and safe regimen for the treatment of ABS.

The authors would like to thank the investigators who partici-pated in this clinical trial. We would also like to thank AdvancedBiologics, LLC (New Hope, PA) for data analysis. We thankJonathan Cargan, MD of Phoenix Ascendant Consulting, LLC(Norristown, PA) for manuscript development and associated ser-vices.

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