Azithromycin and Amoxicillin of Acute Maxillary Sinusitis ROY
R. CASIANO,
M.D.,
in the Treatment
Miami, Florida
Seventy-eight patients participated in this mulzithromycin is an azalide antibiotic that is ticenter, third-party-blinded study comparing a chemically related to erythromycin but demsingle daily dose of azithromycin for 5 days onstratessignificant microbiologicand pharmacoki(500 mg on day 1 followed by 250 mg/day for netic differencesfrom this class of agents. The indays 2-5) with amoxicillin (500mg three times sertion of a methylated nitrogen group at position 9 daily) for 10 days in the treatment of acute of the aglycone ring confers on the molecule inbacterial maxillary sinusitis. A total of 38 eval- creasedacid stability El] and excellent bioavailabiluable patients contributed to the efficacy anal- ity [Z]. Azithromycin has a broad spectrum of activysis. The overall clinical response rate was ity, with coverage of many Gram-positive organ100%for both antibiotics. The clinical cure isms and excellent activity againstsomekey Gramrate, as determined by the investigator, was negative pathogens,including Haemophilus influ73.9%for azithromycin and 73.3%for amoxicil- enzae[3,41.Oropharyngealanaerobesare also suslin; improvement was seen in 26.1% and 26.7% ceptible to azithromycin [3]. The unique pharmacoof patients, respectively. The bacteriologic cure kinetics of this drug are characterizedby high intracellular and tissue concentrations, but low rate in these 38 patients was 100%in both groups. Both antibiotics were well tolerated; serum concentrations. Phagocytic cells take up azithromycin and migrate to sites of infection, furside effects ivere reported by 4.9% of patients in the azithromycin group compared with 8.1% ther enhancingdrug concentrationsat the infected in the amoxicillin group. Most of these side focus [5]. effects were gastrointestinal disturbances that In clinical pharmacokineticstudies, high levels of were reported by four of five (three amoxicilazithromycin have been attained in the sinus fluid lin, one azithromycin) patients experiencing and tissues of patients with acute or chronic sinusiside effects. All side effects were mild, and in tis. Levels remainedhigh up to 4 days postdoseand both groups only minor abnormalities in labowere higher in patients with acute sinusitis than in ratory data were detected. No patient disconthose with chronic disease, suggesting that the drug is more effectively delivered to acutely intinued the study becauseof treatment-related flamed tissues [6]. side effects. In this study, a B-day course (one A recent European clinical trial comparing the dose per day) of azithromycin proved to have efficacy, safety, and tolerability that was equal efficacy of azithromycin and amoxicillin in patients with acute sinusitis demonstrated that a 5-day to a lo-day course (three doses per day) of amoxicillin in the treatment of acute bacterial (five-dose)courseof azithromycin was comparable, sinusitis. in terms of clinical and bacteriologic efficacy, to a lo-day (30-dose)course of amoxicillin [?‘I. The purposeof this study, conductedat 13 centers, was to further compare azithromycin and amoxicillin in the treatment of patients with acute bacterial sinusitis.
A
From the Department of Otolaryngology, University of Miami/Jackson Memorial Medical Center, Miami, Florida. This work was supported by a research grant from Pfizer Central Research, Groton, Connecticut, USA. Requests for reprints should be addressed to Roy R. Casiano, M.D., Department of Otolaryngology, University of Miami/Jackson Memorial Medical Center, PO Box 16960-6960, Miami, Florida 33101.
September
PATIENTSAND METHODS Patients aged 16 years or more with a clinical diagnosisof an acute episodeof bacterial maxillary sinusitis were eligible to enter this study. Female patients were eligible to enter the trial providing they were not lactating or pregnant. Informed consent was obtainedfrom all patients. The main exclusioncriteria in this study were: known hypersensitivity or intoleranceto macrolide or penicillin an12, 1991
The American Journal of Medicine
Volume 91 (suppl 3A)
3A-27s
SYMPOSIUMON TISSUE-DIRECTED ANTIBIOTICTHERAPYI CABIANO
tibiotics; any history of chronic sinusitis; peptic ulcers or any other condition affecting drug absorption; and treatment within the previous 72 hours with any other antibiotic. The clinical diagnosis was confirmed by the presence of a bacterial isolate in sinus fluid obtained by transantral aspiration of the maxillary sinus. Patients were randomly assigned to drug treatment by a third party to prevent the investigator from knowing the patient’s study medication. Patients were allocated in equal numbers to the two treatment groups. If treatment randomization was delayed until the results of the bacteriology testing were known, then the causative organism must have-been susceptible to both drugs. However, if patients were allocated to treatment before the bacteriol&gic results were available, then the pathogen had only to be susceptible to the assigned drug. Patient response to treatment was monitored by assessing clinical parameters at baseline and on study days 6 (? 1 day), 11 (between days 10 and 13), 18 (+l day), and 30 (+l day). Overall clinical outcome to therapy was evaluated on day 11. Signs and symptoms assessed were fever, sinus tenderness and pain, headache, and purulent nasal discharge. Clinical response was classified as follows: Satisfactory: A patient was cured if signs and symptoms of infection resolved during the study with no evidence of infection at day 11 (days 10 to 13). Improvement was judged to be subsidence of signs and symptoms during the study but with incomplete resolution by day 11 (days 10-13). Unsatisfactory: Failure of therapy with no apparent clinical response at day 11. Bacterial eradication was defined as elimination of the initial causative pathogen by day 11 (days 10 to 13). Transantral aspiration of the maxillary sinus for culture and susceptibility studies was performed at baseline. However, because of the invasive nature of the procedure, it was only repeated if the patient had not responded to treatment by day 11. A repeat transantral procedure was performed to determine whether the failure was due to persistence of the original causative pathogen (or pathogens). Normalization of sinus opacity, based on transillumination and radiographs, together with the resolution of clinical findings, were taken to be equivalent to a negative culture. Susceptibility of causative organisms to the study drugs was determined using the Kirby-Bauer method (disk-diffusion or broth dilution methods). For the purposes of this study, the criteria for determining susceptibility to azithromycin (15 pg disks) were: zone-inhibition diameters of r 18 mm for susceptible category; 14-17 mm for intermediate category; and 113 mm 3A-28s
September
12, 1991
The American Journal of Medicine
for resistant organisms. The corresponding minimum inhibitory concentrations were 52 mg/L, 4 mg/L, and 28 mg/L, respectively. Side effects were assessed at all visits and laboratory safety tests (hematology, biochemistry, urinalysis) were performed at baseline and on each follow-up visit. A total of 78 patients were enrolled at 13 centers. Forty-one (21 males, 20 females) patients were treated with azithromycin (500 mg on day 1, followed by 250 mg on days 2-5, as a single daily dose) and 37 (18 males, 19 females) patients were treated with amoxicillin (500 mg three times daily for 10 days). The mean age of the azithromycin patients was 37.7 (range, 16-69) years compared with 38.1 (range, 20-73) years in the amoxicillin patients. This study was conducted in compliance with institutional review board and informed consent regulations.
RESULTS A total of 78 (azithromycin 41, amoxicillin 37) patients entered the study. Four patients receiving azithromycin and nine in the amoxicillin group discontinued treatment because they did not meet entry criteria. Of the remaining 65 patients who completed the trial, 14 in the azithromycin group and 13 in the amoxicillin group were excluded from the analysis. Most of these patients were excluded because there was no evidence of a baseline pathogen or because susceptibility tests were not performed. Only one patient in the azithromycin group was excluded from the analysis because of a resistant pathogen, whereas this was the reason for exclusion in 11 patients receiving amoxicillin. The efficacy data for this study is therefore based on a total of 38 evaluable patients. Twenty-three (56%) of the azithromycin patients were evaluable compared with 15 (41%) of the amoxicillin patients. The investigators’ opinion of clinical response at the end of therapy (day 11) in the evaluable group of patients is shown in Table I. The results in the two treatment groups were virtually identical. The clinical cure rate measured on day 11 but after only 5 days’ treatment with once daily azithromycin was 73.9% compared to 73.3% after 10 days’ three times daily treatment with amoxicillin. All the remaining patients improved and there were no treatment failures. Fourteen organisms were identified in the 38 evaluable patients across the two treatment groups (Table II). The most common isolates in the azithromycin group were coagulase-negative Staphylococcus (6 of 27 isolates), Staphylococcus aureus (5 of 27), Streptococcus pyogenes (4 of 27),
Volume 91 (suppl 3A)
and alpha-hemolyticStreptococcus (4 of 27). In the amoxicillin group, alpha-hemolytic Streptococcus accountedfor 6 of 16 of the isolated organisms, S. aureus being the next most common(2 of 16). Surprisingly, only one Haemophilus spp. (H. parainjluenxae) was found in the group of patients studied. The absenceof Haemophilus in$!uenxae isolates is notable. Since culture was performed after overnight air shipment to a central laboratory, it is possiblethat transport-related factors led to nonviability of H. in.uenxae isolates.Many of the organisms isolated by maxillary puncture were not typical of pathogensusually associatedwith acute sinusitis. Nevertheless,while recognizingthese concerns,the bacteriologiccure rate at the end of therapy for the evaluable patients was 100% in both treatment groups. The safety data reports are based on the 78 patients who took at least one doseof study medication. Five patients reported a total of six side effects. In the azithromycin group, 2 of 41 (4.9%)patients reported a total of three side effects;two patients complainedof headacheand one of these patients also experiencednausea. In the amoxicillin group, 3 of 37 (8.1%)patients reported gastrointestinal disturbances(diarrhea, loose stools, and dyspepsia).All the reported side effectswere mild and none of the patients withdrew from the study due to an adverse effect of therapy. A number of minor isolated abnormalities occurred in the wide range of laboratory tests undertaken during the study. Treatment-related abnormalities occurred in 3 of 38 (8%) of azithromycintreated patients and in 5 of 3’7(14%)of amoxicillintreated patients. Chiefly, the changesseenwere in white blood cell count and in liver enzymes,the latter being elevated. Two (4.9%) patients receiving azithromycin and four (10.8%)patients receiving amoxicillin had concurrent diseases.In the azithromycin group, one patient had a cold and cough and the other had recurrent sinusitis that was found to be causedby an organism different from the one cultured pretreatment. In the amoxicillin group, the four patients experiencedthe following: chest pain and chronic ischemic heart disease; cough and ear disorder; bronchitis; and an impacted wisdom tooth. In conclusion,azithromycin is a novel antibiotic with distinct in vitro and pharmacokineticfeatures. It is known to penetrateeffectively into sinustissue and there is evidence to suggest that additional quantities of the drug are delivered by phagocytes to acutely inflamed tissue preferentially [5,6]. As a result of azithromycin’s high tissue bioactivity, short dosing regimens that provide clear patient benefits are possible. September
TABLEI Investigators’Assessmentof ClinicalResponseat the End of lIe;~; (Day 11) in the 38 BacteriologicallyEvaluable Treatment Group Aziiromycin Clinical Response Cured
$yd Total evaluable
Amoxiciflin %
No.
%
26.1
73.9
11 i
13.3 26.7
Iii.0
15
loo.0
No. 17
:
23
TABLEII Responseof SinusPuncture Isolatesat the End of Therapy Treatment Groep Azithromycin Pathogen
Eradicated
Amoxicillin Total
Eradicated
Total
0
0
1
1
t 0
! 0
:
;
6
6
25
2”
A
il
:
:
lfacteroides spp. MoraxeUa(&a&neHa) catarMs Escherichia co/i Haemophlus parainknzae Coaiylase-negative Sfap~OCCCCllS Staphylococcla aureus Sta~yfococcus epidemidb Stfepfococcus anginosus Streptococcus motillorum Sifeptococcf6 pneumoniae Streptococcus pyogeftes Streptccoccus group D Alpha-hemolytic Streptfococcs Beta-hemolytic group F All pathogens
::
1
4
1
I
:
:
i
i
A
A
1
A
A
4
6
6
streptacKclJs
::
1;
1:
This study of patients with radiographically documented acute bacterial sinusitis has shown that only five dosesof azithromycin over 5 days was as effective as a 30-dosecourse of amoxicillin given over 10 days. Eradication of bacterial isolates was 100%.Although H. injluenzae was not recoveredin this study, a previousinvestigation of azithromycin in the treatment of maxillary sinusitis demonstrated 95%(19of 20)eradicationof antral H. influenzae isolates [7]. In the present study, azithromycin demonstratedexcellent tolerability andits short-courseregimen is expected to offer the advantage of improved patient compliance. ACKNOWLEDGMENTS The 13 investigators who recruited patients into this study are gratefully acknowledged. The active participants were: Dr. R. R. Casiano, Jackson Memorial Hospital, Department of Dtolaryngology, 1666 N.W. 10th Ave. AC.C. East Building 306, Miami, FL 33136; Dr. L. E. Ellinwood, St. Mary’s Hospital & Medical Center, Family Practice Residency Program, 2333 North Sixth Street, Grand Junction, CO 81501; Dr. L. Feiner. Valley Forge Facial Plastic Surgery, 2023 East High Street, Pottstown,
12,
1991 The American Journal of Medicine
Volume
91 (suppl 3A)
3A-29s
SYMPOSIUMON TISSUE-DIRECTED ANTIBIOTICTHERAPY/ CASIANO PA 19464; Dr R. J. Fieman, 4545 E. 9th Avenue, Suite 200, Denver, CO 80220; Dr. N. A. Garrison, National Industries, 2745 Gunter Park Drive, West Montgomery, AL 36109; Dr. P. Johnson, Ear, Nose and Throat Consultants of Winchester, 116 Medical Circle, Winchester, VA 22601; Dr. R. G. Love, The Dtorhinolaryngology Associates, P.C., 2173 Normandie Drive, Montgomery, AL 36198; Dr. L. E. Mansfield, El Paso Institute for Medical Research and Development, Suite 2400, 1800 Curie Drive, El Paso, TX 79902; Dr. W. Menvin, The Nalle Clinic, 1350 S. Kings Drive, Charlotte, NC 28207; Dr. L. H. Repsher, Lutheran Medical Center, 8300 W. 38th Avenue, Wheat Ridge, CO 80033; Dr. W. S. Silvers, 7180 E. Orchard Road, Englewood, CO 80111; Dr. T. Simpkins, 652 Lomb Avenue, Birmingham, AL 35211; Dr M. A. Tralla, 3550 Lutheran Parkway West, Suite 102, Wheatridge, CD 80033.
REFERENCES 1. Fiese EF, Steffen SH. Comparison of the acid stability of azithromycin and erythromycin A. J Antimicrob Chemother 1990; 25 (Suppl A): 39-47. 2. Foulds G, Shepard RM, Johnson RB. The pharmacokinetics of azithromycin in
3A-3oS
September
12,
1991
The American Journal of Medicine
Volume
human serum and tissues. J Antimicrab Chemother 1990; 25 (Suppl A): 73-82. 3. Retsema J, Girard A, Schelkley W, ef al. Spectrum and mode of action of azithromycin (CP-62,993) a new 15.membered-ring macrolide with improved potency against gram-negative organisms. Antimicrob Agents Chemother 1987; 31: 1937-47. 4. Arnoff SC, Laurent C, Jacobs MR. In vitro activity of erythromycin, roxithromycin and CP-62,993 against common pediatric pathogens. J Antimicrob Chemother 1987; 19: 275-6. 5. Gladue RP, Bright GM, lsaacson RE, Newborg MF. In vitro and in vivo uptake of azithromycin (CP-62,993) by phagocytic cells: possible mechanism of delivery and release at sites of infection Antimicrob Agents Chemother 1989; 33: 277-82. 6. Pukander J, Karma P, Penttila M. Azithromycin concentrations in sinus fluid and mucosa after oral azithromycin. 7th Mediterranean Congress of Chemotherapy (abstract), Barcelona, Spain, May 20-25, 1990. 7. Felstead SJ. Efficacy, safety and toleration of atithromycin and amoxrcillin in the treatment of acute sinusitis. 7th Mediterranean Congress of Chemotherapy (abstract), Barcelona, Spain, May 20-25, 1990.
91 (suppl
3A)
R. CASIANO,
M.D.,
in the Treatment
Miami, Florida
Seventy-eight patients participated in this mulzithromycin is an azalide antibiotic that is ticenter, third-party-blinded study comparing a chemically related to erythromycin but demsingle daily dose of azithromycin for 5 days onstratessignificant microbiologicand pharmacoki(500 mg on day 1 followed by 250 mg/day for netic differencesfrom this class of agents. The indays 2-5) with amoxicillin (500mg three times sertion of a methylated nitrogen group at position 9 daily) for 10 days in the treatment of acute of the aglycone ring confers on the molecule inbacterial maxillary sinusitis. A total of 38 eval- creasedacid stability El] and excellent bioavailabiluable patients contributed to the efficacy anal- ity [Z]. Azithromycin has a broad spectrum of activysis. The overall clinical response rate was ity, with coverage of many Gram-positive organ100%for both antibiotics. The clinical cure isms and excellent activity againstsomekey Gramrate, as determined by the investigator, was negative pathogens,including Haemophilus influ73.9%for azithromycin and 73.3%for amoxicil- enzae[3,41.Oropharyngealanaerobesare also suslin; improvement was seen in 26.1% and 26.7% ceptible to azithromycin [3]. The unique pharmacoof patients, respectively. The bacteriologic cure kinetics of this drug are characterizedby high intracellular and tissue concentrations, but low rate in these 38 patients was 100%in both groups. Both antibiotics were well tolerated; serum concentrations. Phagocytic cells take up azithromycin and migrate to sites of infection, furside effects ivere reported by 4.9% of patients in the azithromycin group compared with 8.1% ther enhancingdrug concentrationsat the infected in the amoxicillin group. Most of these side focus [5]. effects were gastrointestinal disturbances that In clinical pharmacokineticstudies, high levels of were reported by four of five (three amoxicilazithromycin have been attained in the sinus fluid lin, one azithromycin) patients experiencing and tissues of patients with acute or chronic sinusiside effects. All side effects were mild, and in tis. Levels remainedhigh up to 4 days postdoseand both groups only minor abnormalities in labowere higher in patients with acute sinusitis than in ratory data were detected. No patient disconthose with chronic disease, suggesting that the drug is more effectively delivered to acutely intinued the study becauseof treatment-related flamed tissues [6]. side effects. In this study, a B-day course (one A recent European clinical trial comparing the dose per day) of azithromycin proved to have efficacy, safety, and tolerability that was equal efficacy of azithromycin and amoxicillin in patients with acute sinusitis demonstrated that a 5-day to a lo-day course (three doses per day) of amoxicillin in the treatment of acute bacterial (five-dose)courseof azithromycin was comparable, sinusitis. in terms of clinical and bacteriologic efficacy, to a lo-day (30-dose)course of amoxicillin [?‘I. The purposeof this study, conductedat 13 centers, was to further compare azithromycin and amoxicillin in the treatment of patients with acute bacterial sinusitis.
A
From the Department of Otolaryngology, University of Miami/Jackson Memorial Medical Center, Miami, Florida. This work was supported by a research grant from Pfizer Central Research, Groton, Connecticut, USA. Requests for reprints should be addressed to Roy R. Casiano, M.D., Department of Otolaryngology, University of Miami/Jackson Memorial Medical Center, PO Box 16960-6960, Miami, Florida 33101.
September
PATIENTSAND METHODS Patients aged 16 years or more with a clinical diagnosisof an acute episodeof bacterial maxillary sinusitis were eligible to enter this study. Female patients were eligible to enter the trial providing they were not lactating or pregnant. Informed consent was obtainedfrom all patients. The main exclusioncriteria in this study were: known hypersensitivity or intoleranceto macrolide or penicillin an12, 1991
The American Journal of Medicine
Volume 91 (suppl 3A)
3A-27s
SYMPOSIUMON TISSUE-DIRECTED ANTIBIOTICTHERAPYI CABIANO
tibiotics; any history of chronic sinusitis; peptic ulcers or any other condition affecting drug absorption; and treatment within the previous 72 hours with any other antibiotic. The clinical diagnosis was confirmed by the presence of a bacterial isolate in sinus fluid obtained by transantral aspiration of the maxillary sinus. Patients were randomly assigned to drug treatment by a third party to prevent the investigator from knowing the patient’s study medication. Patients were allocated in equal numbers to the two treatment groups. If treatment randomization was delayed until the results of the bacteriology testing were known, then the causative organism must have-been susceptible to both drugs. However, if patients were allocated to treatment before the bacteriol&gic results were available, then the pathogen had only to be susceptible to the assigned drug. Patient response to treatment was monitored by assessing clinical parameters at baseline and on study days 6 (? 1 day), 11 (between days 10 and 13), 18 (+l day), and 30 (+l day). Overall clinical outcome to therapy was evaluated on day 11. Signs and symptoms assessed were fever, sinus tenderness and pain, headache, and purulent nasal discharge. Clinical response was classified as follows: Satisfactory: A patient was cured if signs and symptoms of infection resolved during the study with no evidence of infection at day 11 (days 10 to 13). Improvement was judged to be subsidence of signs and symptoms during the study but with incomplete resolution by day 11 (days 10-13). Unsatisfactory: Failure of therapy with no apparent clinical response at day 11. Bacterial eradication was defined as elimination of the initial causative pathogen by day 11 (days 10 to 13). Transantral aspiration of the maxillary sinus for culture and susceptibility studies was performed at baseline. However, because of the invasive nature of the procedure, it was only repeated if the patient had not responded to treatment by day 11. A repeat transantral procedure was performed to determine whether the failure was due to persistence of the original causative pathogen (or pathogens). Normalization of sinus opacity, based on transillumination and radiographs, together with the resolution of clinical findings, were taken to be equivalent to a negative culture. Susceptibility of causative organisms to the study drugs was determined using the Kirby-Bauer method (disk-diffusion or broth dilution methods). For the purposes of this study, the criteria for determining susceptibility to azithromycin (15 pg disks) were: zone-inhibition diameters of r 18 mm for susceptible category; 14-17 mm for intermediate category; and 113 mm 3A-28s
September
12, 1991
The American Journal of Medicine
for resistant organisms. The corresponding minimum inhibitory concentrations were 52 mg/L, 4 mg/L, and 28 mg/L, respectively. Side effects were assessed at all visits and laboratory safety tests (hematology, biochemistry, urinalysis) were performed at baseline and on each follow-up visit. A total of 78 patients were enrolled at 13 centers. Forty-one (21 males, 20 females) patients were treated with azithromycin (500 mg on day 1, followed by 250 mg on days 2-5, as a single daily dose) and 37 (18 males, 19 females) patients were treated with amoxicillin (500 mg three times daily for 10 days). The mean age of the azithromycin patients was 37.7 (range, 16-69) years compared with 38.1 (range, 20-73) years in the amoxicillin patients. This study was conducted in compliance with institutional review board and informed consent regulations.
RESULTS A total of 78 (azithromycin 41, amoxicillin 37) patients entered the study. Four patients receiving azithromycin and nine in the amoxicillin group discontinued treatment because they did not meet entry criteria. Of the remaining 65 patients who completed the trial, 14 in the azithromycin group and 13 in the amoxicillin group were excluded from the analysis. Most of these patients were excluded because there was no evidence of a baseline pathogen or because susceptibility tests were not performed. Only one patient in the azithromycin group was excluded from the analysis because of a resistant pathogen, whereas this was the reason for exclusion in 11 patients receiving amoxicillin. The efficacy data for this study is therefore based on a total of 38 evaluable patients. Twenty-three (56%) of the azithromycin patients were evaluable compared with 15 (41%) of the amoxicillin patients. The investigators’ opinion of clinical response at the end of therapy (day 11) in the evaluable group of patients is shown in Table I. The results in the two treatment groups were virtually identical. The clinical cure rate measured on day 11 but after only 5 days’ treatment with once daily azithromycin was 73.9% compared to 73.3% after 10 days’ three times daily treatment with amoxicillin. All the remaining patients improved and there were no treatment failures. Fourteen organisms were identified in the 38 evaluable patients across the two treatment groups (Table II). The most common isolates in the azithromycin group were coagulase-negative Staphylococcus (6 of 27 isolates), Staphylococcus aureus (5 of 27), Streptococcus pyogenes (4 of 27),
Volume 91 (suppl 3A)
and alpha-hemolyticStreptococcus (4 of 27). In the amoxicillin group, alpha-hemolytic Streptococcus accountedfor 6 of 16 of the isolated organisms, S. aureus being the next most common(2 of 16). Surprisingly, only one Haemophilus spp. (H. parainjluenxae) was found in the group of patients studied. The absenceof Haemophilus in$!uenxae isolates is notable. Since culture was performed after overnight air shipment to a central laboratory, it is possiblethat transport-related factors led to nonviability of H. in.uenxae isolates.Many of the organisms isolated by maxillary puncture were not typical of pathogensusually associatedwith acute sinusitis. Nevertheless,while recognizingthese concerns,the bacteriologiccure rate at the end of therapy for the evaluable patients was 100% in both treatment groups. The safety data reports are based on the 78 patients who took at least one doseof study medication. Five patients reported a total of six side effects. In the azithromycin group, 2 of 41 (4.9%)patients reported a total of three side effects;two patients complainedof headacheand one of these patients also experiencednausea. In the amoxicillin group, 3 of 37 (8.1%)patients reported gastrointestinal disturbances(diarrhea, loose stools, and dyspepsia).All the reported side effectswere mild and none of the patients withdrew from the study due to an adverse effect of therapy. A number of minor isolated abnormalities occurred in the wide range of laboratory tests undertaken during the study. Treatment-related abnormalities occurred in 3 of 38 (8%) of azithromycintreated patients and in 5 of 3’7(14%)of amoxicillintreated patients. Chiefly, the changesseenwere in white blood cell count and in liver enzymes,the latter being elevated. Two (4.9%) patients receiving azithromycin and four (10.8%)patients receiving amoxicillin had concurrent diseases.In the azithromycin group, one patient had a cold and cough and the other had recurrent sinusitis that was found to be causedby an organism different from the one cultured pretreatment. In the amoxicillin group, the four patients experiencedthe following: chest pain and chronic ischemic heart disease; cough and ear disorder; bronchitis; and an impacted wisdom tooth. In conclusion,azithromycin is a novel antibiotic with distinct in vitro and pharmacokineticfeatures. It is known to penetrateeffectively into sinustissue and there is evidence to suggest that additional quantities of the drug are delivered by phagocytes to acutely inflamed tissue preferentially [5,6]. As a result of azithromycin’s high tissue bioactivity, short dosing regimens that provide clear patient benefits are possible. September
TABLEI Investigators’Assessmentof ClinicalResponseat the End of lIe;~; (Day 11) in the 38 BacteriologicallyEvaluable Treatment Group Aziiromycin Clinical Response Cured
$yd Total evaluable
Amoxiciflin %
No.
%
26.1
73.9
11 i
13.3 26.7
Iii.0
15
loo.0
No. 17
:
23
TABLEII Responseof SinusPuncture Isolatesat the End of Therapy Treatment Groep Azithromycin Pathogen
Eradicated
Amoxicillin Total
Eradicated
Total
0
0
1
1
t 0
! 0
:
;
6
6
25
2”
A
il
:
:
lfacteroides spp. MoraxeUa(&a&neHa) catarMs Escherichia co/i Haemophlus parainknzae Coaiylase-negative Sfap~OCCCCllS Staphylococcla aureus Sta~yfococcus epidemidb Stfepfococcus anginosus Streptococcus motillorum Sifeptococcf6 pneumoniae Streptococcus pyogeftes Streptccoccus group D Alpha-hemolytic Streptfococcs Beta-hemolytic group F All pathogens
::
1
4
1
I
:
:
i
i
A
A
1
A
A
4
6
6
streptacKclJs
::
1;
1:
This study of patients with radiographically documented acute bacterial sinusitis has shown that only five dosesof azithromycin over 5 days was as effective as a 30-dosecourse of amoxicillin given over 10 days. Eradication of bacterial isolates was 100%.Although H. injluenzae was not recoveredin this study, a previousinvestigation of azithromycin in the treatment of maxillary sinusitis demonstrated 95%(19of 20)eradicationof antral H. influenzae isolates [7]. In the present study, azithromycin demonstratedexcellent tolerability andits short-courseregimen is expected to offer the advantage of improved patient compliance. ACKNOWLEDGMENTS The 13 investigators who recruited patients into this study are gratefully acknowledged. The active participants were: Dr. R. R. Casiano, Jackson Memorial Hospital, Department of Dtolaryngology, 1666 N.W. 10th Ave. AC.C. East Building 306, Miami, FL 33136; Dr. L. E. Ellinwood, St. Mary’s Hospital & Medical Center, Family Practice Residency Program, 2333 North Sixth Street, Grand Junction, CO 81501; Dr. L. Feiner. Valley Forge Facial Plastic Surgery, 2023 East High Street, Pottstown,
12,
1991 The American Journal of Medicine
Volume
91 (suppl 3A)
3A-29s
SYMPOSIUMON TISSUE-DIRECTED ANTIBIOTICTHERAPY/ CASIANO PA 19464; Dr R. J. Fieman, 4545 E. 9th Avenue, Suite 200, Denver, CO 80220; Dr. N. A. Garrison, National Industries, 2745 Gunter Park Drive, West Montgomery, AL 36109; Dr. P. Johnson, Ear, Nose and Throat Consultants of Winchester, 116 Medical Circle, Winchester, VA 22601; Dr. R. G. Love, The Dtorhinolaryngology Associates, P.C., 2173 Normandie Drive, Montgomery, AL 36198; Dr. L. E. Mansfield, El Paso Institute for Medical Research and Development, Suite 2400, 1800 Curie Drive, El Paso, TX 79902; Dr. W. Menvin, The Nalle Clinic, 1350 S. Kings Drive, Charlotte, NC 28207; Dr. L. H. Repsher, Lutheran Medical Center, 8300 W. 38th Avenue, Wheat Ridge, CO 80033; Dr. W. S. Silvers, 7180 E. Orchard Road, Englewood, CO 80111; Dr. T. Simpkins, 652 Lomb Avenue, Birmingham, AL 35211; Dr M. A. Tralla, 3550 Lutheran Parkway West, Suite 102, Wheatridge, CD 80033.
REFERENCES 1. Fiese EF, Steffen SH. Comparison of the acid stability of azithromycin and erythromycin A. J Antimicrob Chemother 1990; 25 (Suppl A): 39-47. 2. Foulds G, Shepard RM, Johnson RB. The pharmacokinetics of azithromycin in
3A-3oS
September
12,
1991
The American Journal of Medicine
Volume
human serum and tissues. J Antimicrab Chemother 1990; 25 (Suppl A): 73-82. 3. Retsema J, Girard A, Schelkley W, ef al. Spectrum and mode of action of azithromycin (CP-62,993) a new 15.membered-ring macrolide with improved potency against gram-negative organisms. Antimicrob Agents Chemother 1987; 31: 1937-47. 4. Arnoff SC, Laurent C, Jacobs MR. In vitro activity of erythromycin, roxithromycin and CP-62,993 against common pediatric pathogens. J Antimicrob Chemother 1987; 19: 275-6. 5. Gladue RP, Bright GM, lsaacson RE, Newborg MF. In vitro and in vivo uptake of azithromycin (CP-62,993) by phagocytic cells: possible mechanism of delivery and release at sites of infection Antimicrob Agents Chemother 1989; 33: 277-82. 6. Pukander J, Karma P, Penttila M. Azithromycin concentrations in sinus fluid and mucosa after oral azithromycin. 7th Mediterranean Congress of Chemotherapy (abstract), Barcelona, Spain, May 20-25, 1990. 7. Felstead SJ. Efficacy, safety and toleration of atithromycin and amoxrcillin in the treatment of acute sinusitis. 7th Mediterranean Congress of Chemotherapy (abstract), Barcelona, Spain, May 20-25, 1990.
91 (suppl
3A)
