Azithromycin Compared with Cephalexin in the Treatment of Skin and Skin Structure Infections SUSAN
B.
MALLORY,
M.D.,
st LOUS,
Missouri
This randomized, third-party-blinded study compared short-course therapy of once-daily azithromycin (500 mg on day 1, followed by 250 mgiday on days 2-5) with cephalexin (500 mg twice daily for 10 days) in the treatment of patients with skin and skin structure infections. At 25 centers, a total of 361 patients were entered into the study and 148 were evaluable for efficacy. The main causative pathogens, Staphylococcus aureus and Streptococcus pyoyenes, were responsible for approximately two thirds of the infections in the two treatment groups. Clinical cure and improvement rates for the two treatments were comparable: 99% with azithromycin and 96% with cephalexin. On completion of therapy, both treatments had eradicated approximately 98% of pathogens. In general, both agents were welltolerated. The results of this study show that a 5-day course of once-daily treatment with azithromycin is as effective as a lo-day course of twice-daily treatment with cephalexin in the management of skin and skin structure infections.
A
zithromycin is the first of a new class of antimicrobial agents called the azalides, developed for short-course therapy of a wide range of infections [l]. Chemically related to erythromycin, it has similar Gram-positive activity but a broader spectrum of activity against anaerobes and Gram-negative bacteria, including Escherichia coli, Haemophilus influenxae, and Klebsiella pneumoniae [2]. Azithromycin is an acid-stable compound that produces high and sustained concentrations in the tissues even though serum levels are extremely low [3,4]. The drug’s half-life in the tissues is approximately 2-4 days, and in inflammatory fluid, such as that produced by cantharidin-induced blisters, rapid penetration and prolonged levels are found [5]. In vitro studies have shown that this compound is active against skin and skin structure pathogens such as Staphylococcus aureus and Staphylococcus epidermidis [6]. Azithromycin’s high tissue penetration and prolonged tissue concentration allow once-a-day dosing and a short 5-day course of therapy. The purpose of this multicenter clinical study was to compare the safety and efficacy of short-course, once-daily azithromycin therapy with cephalexin (given twice daily for 10 days) in the treatment of patients with infections of the skin or skin structures.
PATIENTSAND METHODS
From the St. Louis Children’s Hospital, St. Louis, Missouri. This work was supported by a research grant from Pfizer Central Research, Requests for reprints should be addressed to Susan Mallory, M.D., St. Louis Children’s Hospital, 400 South Kingshighway, St. Louis, Missouri 63110.
3A-36s
September
12, 1991
The American Journal of Medicine
Patients presenting with acute skin or skin structure infections such as cellulitis, pyoderma, erysipelas, or wound infections were eligible to enter this study. The clinical diagnosis of skin infection was confirmed bacteriologically by the presence of a causative pathogen. Male and female patients who had given informed consent were eligible (other than those pregnant or lactating), providing that they were at least 16 years of age. The main exclusion criteria were known hypersensitivity or intolerance to macrolide or cephalosporin antibiotics, oral or topical antibiotic treatment in the 72 hours prior to the study, acute infection of a chronic skin condition, and presence of infected burns or chronic skin ulcers. Treatment with oral or topical steroids was not permitted during the study.
Volume 91 (suppl 3A)
SYMPOSIUM
Patients who met the trial criteria were randomly allocatedto azithromycin or cephalexinin a 2:l ratio. The randomization procedureswere administered by a third party, thus ensuring investigator blindness.In addition, patients were told not to discussthe nature of their study medicationwith the investigator. In most cases,the results of culture and sensitivity testing were obtained within 48 hours prior to the start of the study treatment. If patients were randomizedto treatment after the culture and sensitivity results were known, then the patient was only included in the analysis providing the organism was sensitive to both test drugs. However, if medical treatment was required urgently, then patients couldbe randomly allocatedto study medication before the culture and sensitivity results were known. Under these circumstances,the causative organism must have beensensitive to the assigned drug. If culture testing failed to show the presence of a causativeorganismor if the pathogenidentified was resistant to the randomly assigneddrug, then the patient was withdrawn from the study. Patients withdrawn from the study for these reasons were subjected to follow-up safety assessments. Clinical responseto study medication was determined by assessingthe clinical parametersof fever, pain at infection site or sites, lymphadenitis, erythema, swelling, and production of exudate, at baselineand on study days 6 (+l day), 11(between days 9 and 14), 18 (21 day), and30 (?l day). Color photographsof the infection site or sites were taken pretreatment and on the last day of therapy. Clinical responsewas classified as follows: Satisfactory: A patient was cured if signs and symptoms of infection resolved during the study with no evidenceof infection at day 11 (days9-14). Improvement was judged to be subsidenceof signs and symptoms during the study but with incomplete resolution by day 11 (days 9-14). Unsatisfactory: Failure of therapy with no apparent clinical responseat day 11. Bacteriologic response was determined by the presenceof pathogensrecordedat the baselineassessmentand the end of the treatment period (day 6 for azithromycin patients and day 11for the cephalexin patients). Bacterial eradication was defined as elimination of the initial causative pathogenby day 11(days9-14). Specimensfor culture were collected by either needle aspiration or biopsy of the infection site. Healing of the infection sites and the absenceof an appropriate source of sampling for culture was consideredto represent bacteriologic cure. Susceptibility of causative organisms to the study drugs was determinedusing the Kirby-Bauer
ON TISSUE-DIRECTED
ANllBlOTlC
THERAPY I MALLORY
TABLEI Primary Diagnosisof EvaluablePatients Treabnent Group Primary Diagnosis
Aziiromycin
Infected wound
Cephalexin
8
3
AbSCeSS
Cellulitis Impetigo Other skin and skin structure infections Total
::
ii 5
1:;
2 2
technique (disk-diffusion and/or broth dilution methods).For the purposesof this study, the criteria for determining susceptibility to azithromycin (15 pg disks) were: zone-inhibition diameters of 218 mm for susceptiblecategory; 14-17mm for intermediate category; and 113 mm for resistant organisms. The correspondingminimum inhibitory concentrationswere 52 mg/L, 4 mg/L, and ~8 mg/L, respectively. Side effectswere assessedat all visits andlaboratory safety tests (hematology,biochemistry, urinalysis) were undertaken at baseline and on each follow-up visit. A total of 363 patients were randomizedto receive study medication. Two patients did not take any medicationor did not return for their follow-up visits. They havenot beenincludedin theseresults. Consequently, 240 patients (133 males, 107 females)received azithromycin (500mg on day 1 followed by 250 mg on days 2-5, all given as single doses)and 121 (64 males, 57 females) patients received cephalexin(500mg twice daily for 10 days) during this study, The meanageof the patients was 40.3(range, 16-89)yearsin the azithromycin group and 39.3 (range, 16-95) years in the cephalexin group. The two predominant primary diagnoses were cellulitis or abscess,which accountedfor approximately 75% of all diagnosesin eachtreatment group. The primary diagnosesare listed in Table I. This study was conductedin compliancewith institutional review board and informed consentregulations. RESULTSAND CONCLUSION At 25 centers throughout the United States, a total of 361 (azithromycin 240;cephalexin 121)patients entered the trial, although213(azithromycin 138;cephalexin75) of these patients could not be included in the efficacy analysis becausethey did not comply with the bacteriologicevaluability criteria. The main reasonsfor exclusionwere absenceof baseline pathogen (96 azithromycin patients; 58 cephalexinpatients) or the presenceof a resistant
September 12, 1991
The American Journal of Medicine
Volume 91 (suppl 3A)
3tI-37s
SYMPOSIUM ON TISSUE-DIRECTED
TABLE
ANflBiOljC
THERAPY I MALLORY
II
Investigators’ Assessment of Clinical Response to Treatment at Day 11 (Days 9-14) Visit TreatmentGroup Aziiromycin Clinical Response Cured Improved Failed Total evaluable
Cephalexin
No.
16
No.
%
68 33
66.7 32.3 1.0 100.0
27 17
58.7 37.0
10:
4.3 loo.0
4:
TABLE III Summary of Bacteriologic
Results
Aziiromycin AsZed
Organisms Staphyhxoccus aureus streptococcus pyogeoes Escherichia coli KM&la pneumoniae
*
^..
Era&ted
Assked
2
:8
35 6
:
:
1
137
.
Eraked
34 6
I
30
Total L
Cephalexin
1:; (98.5%)
;
:;
.
, I
:i (98.3%) 3 .
*inner organtsms: Acmefooacrer cakxaceocus arvfraru$ wnerooacrer caicoaceocus Iwoffi, Acinetobacter spp., Bacteroides capilkws, Bacteroides spp., Citrobacter diversus, Citrobacter spp., Enterobacter agglomerans, Enterobacter cloacae, Enterobacter faecalis Enterobacter sakazakii, Enterobacter spp., Enterococcus, Micrococcus spp., Pasteurella multocida, Peptococcus magnus, Peptostreptococcus asaccharolytcus, Peptostreptococcus spp., beta Streptococcus group 6, group C, group G, beta Streptococcus spp., Streptococcus agalactiae, Streptococcus tnorbit\orum, Streptococcus Mans, Streptococcus
SPP. tThe one failure in this group was a streptococcus group G pathogen.
organism (24 azithromycin, 5 cephalexin).It is not known whether the latter difference is clinically significant, as susceptibility testing breakpointsfor azithromycin are still under investigation. Other reasonsfor exclusion were: no end of therapy assessment (14 azithromycin, 7 cephalexin); inadequate duration of therapy (1 azithromycin, 2 cephalexin); and one patient on cephalexinwas mistakenly entered with laryngitis, Consequently,the efficacy data are basedon the 148evaluablepatients. In the azithromycin group 102 (42.5%) patients were evaluablecomparedwith 46 (34.7%)patients in the cephalexingroup. The investigators’ opinion of clinical responseat the endof therapy (days9-14) is shownin Table II. Sixty-eight (66.7%) patients in the azithromycin group were cured after 5 days’ treatment, according to the investigators’ assessment,and 33 (32.3%) were improved by therapy. There was ane treatment failure only, in a patient with cellulitis, in whom susceptiblestrains of S. aureus and Streptococcusgroup G did not respondto azithromycin. In cephalexin-treatedpatients, 27 (58.7%)were cured and 17 (37.0%)improved after 10 days of therapy. Two failures occurred; onepatient had cellulitis as the primary diagnosis,and one had an abscess.In 3A-38s
September 12,
1991 The American Journal of Medicine
both casesS. aureus was isolated and showedsusceptibility to cephalexin.Onepatient on cephalexin had a recurrent impetigo infection 8 daysafter completing therapy. The principal pathogensidentified in both treatment groups were S. aureus and Streptococcus pyogenes. In the azithromycin-treatedgroup 135of 137(98.5%)pathogenswere eradicatedby the end of the 5-day treatment period. Both failures were from the same patient with cellulitis who had S. aureus and Streptococcus group G as pathogens, both of which were found to be susceptible to azithromycin in vitro. In the cephalexingroup, 58 of 59 (98.3%)pathogenswere treated successfully, the only failure being a S. aureus organism that was susceptiblein vitro. The bacteriologicdata are summarizedin Table III. The safety data reported come from 361patients who took at least one dose of study medication. Overall treatment compliancejn this study. w;t6 good. Azithromycin treatment was scheduledfor 5 days and cephalexintreatment was scheduledfor 10 days; in the azithromycin group (240patients), the meanduration of treatment was 4.8 days andin the cephalexingroup (121patients) it was 9.0 days. A total of 26 of 240 (10.8%) patients in the azithromycin group reported side effects. The majority of these were gastrointestinal disturbances (21 of 26), most of which were mild. Diarrhea, abdominal pain, and nauseawere the main complaints in this group. Two patients (0.8%) in the azithromycingroup withdrew from the study due to the presence of side effects (severe abdominal cramps, vomiting, and nausea;and urticaria). In the cephalexingroup, 6 of 121(5.0%)patients reported side effects, and three (2.5%) withdrew. One patient withdrew after the first day, with a severerash and moderatedyspnea.Two discontinued after two days’ therapy, one with moderate nauseaand vomiting andanotherbecauseof a moderately severerash. Also, in the cephalexingroup, one patient was lost to followw ,aRer&al$ng &he first dose.He died 28 days later as a result of alcohol, cocaine,and opiate intoxication; his death was unrelated to the study medication that he had received. A number of laboratory safety tests showedisolated abnormalities in both groups after therapy. The overall incidence of treatment-related effects was 7% in the azithromycin group and 7% in the cephalexingroup; changesin liver function such as elevatedtransaminasesand total bilirubin were the primary events in both groups. Twenty-eight (12%)patients on azithromycin and 16 (13%)on cephalexinhad concomitant illnesses. In the azithromycin group, one patient had a chla-
Volume 91 (suppl 3A)
SYMPOSIUM
mydial infection and one had candidiasis. In the cephalexin group, one patient had dermatophytosis (primary diagnosis was impetigo). The majority of the other illnesses involved the respiratory system (six patients on azithromycin and five on cephalexin), and the skin and subcutaneous tissue (five and four patients, respectively). This study has shown that a 5-day, once-daily course of therapy with azithromycin, a new azalide antimicrobial, is as effective as a lo-day, twicedaily course of cephalexin in the treatment of patients with skin and skin structure infections.
ACKNOWLEDGMENTS The 25 investigators who recruited patients into this study are gratefully acknowledged. The active participants were: Dr. A. C. Brown, Atlanta Skin and Cancer Clinic, 960 Johnson Ferry Road, Suite 530, Altanta, GA 30342; Dr. J. Bush, PO Box 366, Electic, AL 36024; Dr. G. Carr, Sumrall Medical Clinic, Highway 42 and Center Avenue, Sumrall, MS 39482; Dr. M. Deyo-Svendsen, Red Cedar Clinic SC, 2211 Stout Road, Menomonie, WI 54751; Dr. J. Farrell, Family Medical group, 415 Jungermann Road, St. Peters, MO 63376; Dr. N. A. Garrison Jr, National Industries, 2745 Gunter Park Drive, West Montgomery, AL 36109; Dr. C. M. Geissen, 933 N Charlotte Street, Suite 2A, Pottstown, PA 19464; Dr. L. Gilderman, University Clinical Research Associates, PO Box 840134, 1150 North University Drive Pembroke Pines, FL 33084; Dr. D. Ginsberg, Harleysville Medical Associates, 176 Main Street, Harleysville, PA 19438; Dr. W. M. Gooch Ill, Primary Children’s Medical Center, 320 12th Avenue, Salt Lake City, UT 84103; Dr. A. Graff. 6448 Pembroke Road, PO Box 3572, Hollywood, FL 33023; Dr. S.L. Green, 2122 Executive Drive, Hampton, VA 23666; Dr. N. Heskel, Doctors’ Clinic, 2300 Fifth Avenue, Vero Beach, FL 32960; Dr. C. Holmburg, Medical Associabon Health Center, WlBO N7950 Town Hall Road,
September
ON TISSUE-DIRECTED
ANTIBIOTIC
THERAPY/MALLORY
Menomonee Falls, WI 53051; Dr. T. M. Hooton, Harbotview Medical Center, 325 Ninth Avenue, Seattle, WA 98104; Dr. K. D. Jacobson, Oregon Research group, 1180 Patterson Street, Suite 2A, Eugene, OR 97401; Dr. T. A. Johnson, Clinical Physiology Associates, 3594 Broadway, Suite C, Ft Myers, FL 33901; Dr. S. Mallory, Arkansas Children’s Hospital, BOO Marshall Street, Little Rock, AR 72202; Dr. L. E. Mansfield, El Paso Institute for Medical Research and Development, 1700 Curie Drive, El Paso, TX 79902; Dr. J. W. Nielsen, After Hours Medical Center, 1015 W. Washington Street, Sandusky, OH 44870; Dr. 0. Robinson, Memorial Hospital of Gardena, 1141 West Redondo Beach Blvd., Suite 400, Gardena, CA; Dr. H. Schreiber, 5th Floor Center, St Luke’s Hospital, 11311 Shaker Blvd., Cleveland, OH 45104; Dr; H; Silberman, 470 Biltmore Way, Suite 1, Coral Gables, FL 33134; Dr. N. G. Stevens III, Family Medical Clinic, PO Box 636, 226 Hospital Drive, Jackson, AL 36545; Dr. G. H. Zuckerman, Chafee Medical Center, 4720 Tejon Street, Denver, CO 80211.
REFERENCES 1. Bright GM, Nagel AA, Bordner J, et al. Synthesis, in vitro and in vivo activity of novel 9-deoxo-9a-aza-9a homoerythromycin A derivative; a new class of macrolide antibiobcs, the azalides. J Antibiot 1988; 41: 1029-47. 2. Retsema J, Girard A, Schelkly W, et 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: 1939-47. 3. Girard AE, Girard D, English AR, et al. Pharmacokinetic and in vivo studies with azithromycin (CP-62,993), a new macrolide with an extended half-life and excellent tissue distribution. Antimicrob Agents Chemother 1987; 31: 1948-54. 4. Foulds G, Shepard RM, Johnson RB. The pharmacokinetics of azithromycin in human serum and tissues. J Antimicrob Chemother 1990; 25 (Suppl A): 73-82. 5. Cooper MA, Nye K, Andrews JM, Wise R. The pharmacokinetics and inflammatory fluid penetration of orally administered azithromycin. J Antimicrob Chemother 1990; 26: 533-8. 6. Hardy DJ, Hensey DM, Beyer JM, Vojtko C, McDonald EJ, Fernandes PB. Comparative in vitro activities of new 14., 15., and Idmembered macrolides. Antimicrob Agents Chemother 1988; 32: 1710-g.
12, 1991
The American Journal of Medicine
Volume 91 (suppl 3A)
3A-39s
B.
MALLORY,
M.D.,
st LOUS,
Missouri
This randomized, third-party-blinded study compared short-course therapy of once-daily azithromycin (500 mg on day 1, followed by 250 mgiday on days 2-5) with cephalexin (500 mg twice daily for 10 days) in the treatment of patients with skin and skin structure infections. At 25 centers, a total of 361 patients were entered into the study and 148 were evaluable for efficacy. The main causative pathogens, Staphylococcus aureus and Streptococcus pyoyenes, were responsible for approximately two thirds of the infections in the two treatment groups. Clinical cure and improvement rates for the two treatments were comparable: 99% with azithromycin and 96% with cephalexin. On completion of therapy, both treatments had eradicated approximately 98% of pathogens. In general, both agents were welltolerated. The results of this study show that a 5-day course of once-daily treatment with azithromycin is as effective as a lo-day course of twice-daily treatment with cephalexin in the management of skin and skin structure infections.
A
zithromycin is the first of a new class of antimicrobial agents called the azalides, developed for short-course therapy of a wide range of infections [l]. Chemically related to erythromycin, it has similar Gram-positive activity but a broader spectrum of activity against anaerobes and Gram-negative bacteria, including Escherichia coli, Haemophilus influenxae, and Klebsiella pneumoniae [2]. Azithromycin is an acid-stable compound that produces high and sustained concentrations in the tissues even though serum levels are extremely low [3,4]. The drug’s half-life in the tissues is approximately 2-4 days, and in inflammatory fluid, such as that produced by cantharidin-induced blisters, rapid penetration and prolonged levels are found [5]. In vitro studies have shown that this compound is active against skin and skin structure pathogens such as Staphylococcus aureus and Staphylococcus epidermidis [6]. Azithromycin’s high tissue penetration and prolonged tissue concentration allow once-a-day dosing and a short 5-day course of therapy. The purpose of this multicenter clinical study was to compare the safety and efficacy of short-course, once-daily azithromycin therapy with cephalexin (given twice daily for 10 days) in the treatment of patients with infections of the skin or skin structures.
PATIENTSAND METHODS
From the St. Louis Children’s Hospital, St. Louis, Missouri. This work was supported by a research grant from Pfizer Central Research, Requests for reprints should be addressed to Susan Mallory, M.D., St. Louis Children’s Hospital, 400 South Kingshighway, St. Louis, Missouri 63110.
3A-36s
September
12, 1991
The American Journal of Medicine
Patients presenting with acute skin or skin structure infections such as cellulitis, pyoderma, erysipelas, or wound infections were eligible to enter this study. The clinical diagnosis of skin infection was confirmed bacteriologically by the presence of a causative pathogen. Male and female patients who had given informed consent were eligible (other than those pregnant or lactating), providing that they were at least 16 years of age. The main exclusion criteria were known hypersensitivity or intolerance to macrolide or cephalosporin antibiotics, oral or topical antibiotic treatment in the 72 hours prior to the study, acute infection of a chronic skin condition, and presence of infected burns or chronic skin ulcers. Treatment with oral or topical steroids was not permitted during the study.
Volume 91 (suppl 3A)
SYMPOSIUM
Patients who met the trial criteria were randomly allocatedto azithromycin or cephalexinin a 2:l ratio. The randomization procedureswere administered by a third party, thus ensuring investigator blindness.In addition, patients were told not to discussthe nature of their study medicationwith the investigator. In most cases,the results of culture and sensitivity testing were obtained within 48 hours prior to the start of the study treatment. If patients were randomizedto treatment after the culture and sensitivity results were known, then the patient was only included in the analysis providing the organism was sensitive to both test drugs. However, if medical treatment was required urgently, then patients couldbe randomly allocatedto study medication before the culture and sensitivity results were known. Under these circumstances,the causative organism must have beensensitive to the assigned drug. If culture testing failed to show the presence of a causativeorganismor if the pathogenidentified was resistant to the randomly assigneddrug, then the patient was withdrawn from the study. Patients withdrawn from the study for these reasons were subjected to follow-up safety assessments. Clinical responseto study medication was determined by assessingthe clinical parametersof fever, pain at infection site or sites, lymphadenitis, erythema, swelling, and production of exudate, at baselineand on study days 6 (+l day), 11(between days 9 and 14), 18 (21 day), and30 (?l day). Color photographsof the infection site or sites were taken pretreatment and on the last day of therapy. Clinical responsewas classified as follows: Satisfactory: A patient was cured if signs and symptoms of infection resolved during the study with no evidenceof infection at day 11 (days9-14). Improvement was judged to be subsidenceof signs and symptoms during the study but with incomplete resolution by day 11 (days 9-14). Unsatisfactory: Failure of therapy with no apparent clinical responseat day 11. Bacteriologic response was determined by the presenceof pathogensrecordedat the baselineassessmentand the end of the treatment period (day 6 for azithromycin patients and day 11for the cephalexin patients). Bacterial eradication was defined as elimination of the initial causative pathogenby day 11(days9-14). Specimensfor culture were collected by either needle aspiration or biopsy of the infection site. Healing of the infection sites and the absenceof an appropriate source of sampling for culture was consideredto represent bacteriologic cure. Susceptibility of causative organisms to the study drugs was determinedusing the Kirby-Bauer
ON TISSUE-DIRECTED
ANllBlOTlC
THERAPY I MALLORY
TABLEI Primary Diagnosisof EvaluablePatients Treabnent Group Primary Diagnosis
Aziiromycin
Infected wound
Cephalexin
8
3
AbSCeSS
Cellulitis Impetigo Other skin and skin structure infections Total
::
ii 5
1:;
2 2
technique (disk-diffusion and/or broth dilution methods).For the purposesof this study, the criteria for determining susceptibility to azithromycin (15 pg disks) were: zone-inhibition diameters of 218 mm for susceptiblecategory; 14-17mm for intermediate category; and 113 mm for resistant organisms. The correspondingminimum inhibitory concentrationswere 52 mg/L, 4 mg/L, and ~8 mg/L, respectively. Side effectswere assessedat all visits andlaboratory safety tests (hematology,biochemistry, urinalysis) were undertaken at baseline and on each follow-up visit. A total of 363 patients were randomizedto receive study medication. Two patients did not take any medicationor did not return for their follow-up visits. They havenot beenincludedin theseresults. Consequently, 240 patients (133 males, 107 females)received azithromycin (500mg on day 1 followed by 250 mg on days 2-5, all given as single doses)and 121 (64 males, 57 females) patients received cephalexin(500mg twice daily for 10 days) during this study, The meanageof the patients was 40.3(range, 16-89)yearsin the azithromycin group and 39.3 (range, 16-95) years in the cephalexin group. The two predominant primary diagnoses were cellulitis or abscess,which accountedfor approximately 75% of all diagnosesin eachtreatment group. The primary diagnosesare listed in Table I. This study was conductedin compliancewith institutional review board and informed consentregulations. RESULTSAND CONCLUSION At 25 centers throughout the United States, a total of 361 (azithromycin 240;cephalexin 121)patients entered the trial, although213(azithromycin 138;cephalexin75) of these patients could not be included in the efficacy analysis becausethey did not comply with the bacteriologicevaluability criteria. The main reasonsfor exclusionwere absenceof baseline pathogen (96 azithromycin patients; 58 cephalexinpatients) or the presenceof a resistant
September 12, 1991
The American Journal of Medicine
Volume 91 (suppl 3A)
3tI-37s
SYMPOSIUM ON TISSUE-DIRECTED
TABLE
ANflBiOljC
THERAPY I MALLORY
II
Investigators’ Assessment of Clinical Response to Treatment at Day 11 (Days 9-14) Visit TreatmentGroup Aziiromycin Clinical Response Cured Improved Failed Total evaluable
Cephalexin
No.
16
No.
%
68 33
66.7 32.3 1.0 100.0
27 17
58.7 37.0
10:
4.3 loo.0
4:
TABLE III Summary of Bacteriologic
Results
Aziiromycin AsZed
Organisms Staphyhxoccus aureus streptococcus pyogeoes Escherichia coli KM&la pneumoniae
*
^..
Era&ted
Assked
2
:8
35 6
:
:
1
137
.
Eraked
34 6
I
30
Total L
Cephalexin
1:; (98.5%)
;
:;
.
, I
:i (98.3%) 3 .
*inner organtsms: Acmefooacrer cakxaceocus arvfraru$ wnerooacrer caicoaceocus Iwoffi, Acinetobacter spp., Bacteroides capilkws, Bacteroides spp., Citrobacter diversus, Citrobacter spp., Enterobacter agglomerans, Enterobacter cloacae, Enterobacter faecalis Enterobacter sakazakii, Enterobacter spp., Enterococcus, Micrococcus spp., Pasteurella multocida, Peptococcus magnus, Peptostreptococcus asaccharolytcus, Peptostreptococcus spp., beta Streptococcus group 6, group C, group G, beta Streptococcus spp., Streptococcus agalactiae, Streptococcus tnorbit\orum, Streptococcus Mans, Streptococcus
SPP. tThe one failure in this group was a streptococcus group G pathogen.
organism (24 azithromycin, 5 cephalexin).It is not known whether the latter difference is clinically significant, as susceptibility testing breakpointsfor azithromycin are still under investigation. Other reasonsfor exclusion were: no end of therapy assessment (14 azithromycin, 7 cephalexin); inadequate duration of therapy (1 azithromycin, 2 cephalexin); and one patient on cephalexinwas mistakenly entered with laryngitis, Consequently,the efficacy data are basedon the 148evaluablepatients. In the azithromycin group 102 (42.5%) patients were evaluablecomparedwith 46 (34.7%)patients in the cephalexingroup. The investigators’ opinion of clinical responseat the endof therapy (days9-14) is shownin Table II. Sixty-eight (66.7%) patients in the azithromycin group were cured after 5 days’ treatment, according to the investigators’ assessment,and 33 (32.3%) were improved by therapy. There was ane treatment failure only, in a patient with cellulitis, in whom susceptiblestrains of S. aureus and Streptococcusgroup G did not respondto azithromycin. In cephalexin-treatedpatients, 27 (58.7%)were cured and 17 (37.0%)improved after 10 days of therapy. Two failures occurred; onepatient had cellulitis as the primary diagnosis,and one had an abscess.In 3A-38s
September 12,
1991 The American Journal of Medicine
both casesS. aureus was isolated and showedsusceptibility to cephalexin.Onepatient on cephalexin had a recurrent impetigo infection 8 daysafter completing therapy. The principal pathogensidentified in both treatment groups were S. aureus and Streptococcus pyogenes. In the azithromycin-treatedgroup 135of 137(98.5%)pathogenswere eradicatedby the end of the 5-day treatment period. Both failures were from the same patient with cellulitis who had S. aureus and Streptococcus group G as pathogens, both of which were found to be susceptible to azithromycin in vitro. In the cephalexingroup, 58 of 59 (98.3%)pathogenswere treated successfully, the only failure being a S. aureus organism that was susceptiblein vitro. The bacteriologicdata are summarizedin Table III. The safety data reported come from 361patients who took at least one dose of study medication. Overall treatment compliancejn this study. w;t6 good. Azithromycin treatment was scheduledfor 5 days and cephalexintreatment was scheduledfor 10 days; in the azithromycin group (240patients), the meanduration of treatment was 4.8 days andin the cephalexingroup (121patients) it was 9.0 days. A total of 26 of 240 (10.8%) patients in the azithromycin group reported side effects. The majority of these were gastrointestinal disturbances (21 of 26), most of which were mild. Diarrhea, abdominal pain, and nauseawere the main complaints in this group. Two patients (0.8%) in the azithromycingroup withdrew from the study due to the presence of side effects (severe abdominal cramps, vomiting, and nausea;and urticaria). In the cephalexingroup, 6 of 121(5.0%)patients reported side effects, and three (2.5%) withdrew. One patient withdrew after the first day, with a severerash and moderatedyspnea.Two discontinued after two days’ therapy, one with moderate nauseaand vomiting andanotherbecauseof a moderately severerash. Also, in the cephalexingroup, one patient was lost to followw ,aRer&al$ng &he first dose.He died 28 days later as a result of alcohol, cocaine,and opiate intoxication; his death was unrelated to the study medication that he had received. A number of laboratory safety tests showedisolated abnormalities in both groups after therapy. The overall incidence of treatment-related effects was 7% in the azithromycin group and 7% in the cephalexingroup; changesin liver function such as elevatedtransaminasesand total bilirubin were the primary events in both groups. Twenty-eight (12%)patients on azithromycin and 16 (13%)on cephalexinhad concomitant illnesses. In the azithromycin group, one patient had a chla-
Volume 91 (suppl 3A)
SYMPOSIUM
mydial infection and one had candidiasis. In the cephalexin group, one patient had dermatophytosis (primary diagnosis was impetigo). The majority of the other illnesses involved the respiratory system (six patients on azithromycin and five on cephalexin), and the skin and subcutaneous tissue (five and four patients, respectively). This study has shown that a 5-day, once-daily course of therapy with azithromycin, a new azalide antimicrobial, is as effective as a lo-day, twicedaily course of cephalexin in the treatment of patients with skin and skin structure infections.
ACKNOWLEDGMENTS The 25 investigators who recruited patients into this study are gratefully acknowledged. The active participants were: Dr. A. C. Brown, Atlanta Skin and Cancer Clinic, 960 Johnson Ferry Road, Suite 530, Altanta, GA 30342; Dr. J. Bush, PO Box 366, Electic, AL 36024; Dr. G. Carr, Sumrall Medical Clinic, Highway 42 and Center Avenue, Sumrall, MS 39482; Dr. M. Deyo-Svendsen, Red Cedar Clinic SC, 2211 Stout Road, Menomonie, WI 54751; Dr. J. Farrell, Family Medical group, 415 Jungermann Road, St. Peters, MO 63376; Dr. N. A. Garrison Jr, National Industries, 2745 Gunter Park Drive, West Montgomery, AL 36109; Dr. C. M. Geissen, 933 N Charlotte Street, Suite 2A, Pottstown, PA 19464; Dr. L. Gilderman, University Clinical Research Associates, PO Box 840134, 1150 North University Drive Pembroke Pines, FL 33084; Dr. D. Ginsberg, Harleysville Medical Associates, 176 Main Street, Harleysville, PA 19438; Dr. W. M. Gooch Ill, Primary Children’s Medical Center, 320 12th Avenue, Salt Lake City, UT 84103; Dr. A. Graff. 6448 Pembroke Road, PO Box 3572, Hollywood, FL 33023; Dr. S.L. Green, 2122 Executive Drive, Hampton, VA 23666; Dr. N. Heskel, Doctors’ Clinic, 2300 Fifth Avenue, Vero Beach, FL 32960; Dr. C. Holmburg, Medical Associabon Health Center, WlBO N7950 Town Hall Road,
September
ON TISSUE-DIRECTED
ANTIBIOTIC
THERAPY/MALLORY
Menomonee Falls, WI 53051; Dr. T. M. Hooton, Harbotview Medical Center, 325 Ninth Avenue, Seattle, WA 98104; Dr. K. D. Jacobson, Oregon Research group, 1180 Patterson Street, Suite 2A, Eugene, OR 97401; Dr. T. A. Johnson, Clinical Physiology Associates, 3594 Broadway, Suite C, Ft Myers, FL 33901; Dr. S. Mallory, Arkansas Children’s Hospital, BOO Marshall Street, Little Rock, AR 72202; Dr. L. E. Mansfield, El Paso Institute for Medical Research and Development, 1700 Curie Drive, El Paso, TX 79902; Dr. J. W. Nielsen, After Hours Medical Center, 1015 W. Washington Street, Sandusky, OH 44870; Dr. 0. Robinson, Memorial Hospital of Gardena, 1141 West Redondo Beach Blvd., Suite 400, Gardena, CA; Dr. H. Schreiber, 5th Floor Center, St Luke’s Hospital, 11311 Shaker Blvd., Cleveland, OH 45104; Dr; H; Silberman, 470 Biltmore Way, Suite 1, Coral Gables, FL 33134; Dr. N. G. Stevens III, Family Medical Clinic, PO Box 636, 226 Hospital Drive, Jackson, AL 36545; Dr. G. H. Zuckerman, Chafee Medical Center, 4720 Tejon Street, Denver, CO 80211.
REFERENCES 1. Bright GM, Nagel AA, Bordner J, et al. Synthesis, in vitro and in vivo activity of novel 9-deoxo-9a-aza-9a homoerythromycin A derivative; a new class of macrolide antibiobcs, the azalides. J Antibiot 1988; 41: 1029-47. 2. Retsema J, Girard A, Schelkly W, et 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: 1939-47. 3. Girard AE, Girard D, English AR, et al. Pharmacokinetic and in vivo studies with azithromycin (CP-62,993), a new macrolide with an extended half-life and excellent tissue distribution. Antimicrob Agents Chemother 1987; 31: 1948-54. 4. Foulds G, Shepard RM, Johnson RB. The pharmacokinetics of azithromycin in human serum and tissues. J Antimicrob Chemother 1990; 25 (Suppl A): 73-82. 5. Cooper MA, Nye K, Andrews JM, Wise R. The pharmacokinetics and inflammatory fluid penetration of orally administered azithromycin. J Antimicrob Chemother 1990; 26: 533-8. 6. Hardy DJ, Hensey DM, Beyer JM, Vojtko C, McDonald EJ, Fernandes PB. Comparative in vitro activities of new 14., 15., and Idmembered macrolides. Antimicrob Agents Chemother 1988; 32: 1710-g.
12, 1991
The American Journal of Medicine
Volume 91 (suppl 3A)
3A-39s
