Journal of Antimicrobial Chemotherapy (1990) 25, Suppl.A, 115-121
Comparative studies of azitfaromydn in skin and soft-tissue infections and sexually transmitted infections by Neisseria and Chlamydia species
Hebinki University Central Hospital, Snellmaninkatu 14. 00170 Helsinki, Finland Two open, randomized, single centre studies have investigated the efficacy and safety of azithromycin (CP-62,993) in the treatment of infections by azithromycin-sensitive pathogens: (A) acute bacterial infections of skin or soft tissue (compared with erythromycin; n = 82); and (B) urethritis and/or ccrvicitis caused by Neisseria gonorrhoeae and/or Chlamydia trachomatis (compared with doxycycline; n •»» 108). In study A, azithromycin was administered to 42 patients forfivedays at a dosage of 250 mg bd on day 1 and 250 mg once daily on days 2-5; erythromycin was given to 40 patients for seven days at a dosage of 500 mg every 6 h. In study B, azithromycin was administered either as a single 1 g dose or as a single 500 mg dose on day 1 and 250 mg once daily on days 2 and 3; doxycycline was given at a dose of 100 mg every 12 h for seven days. In study A, 68 patients were clinically assessed: clinical cure or improvement in patients receiving azithromycin or erythromycin was achieved in 86% and 82%, respectively. The principal causative pathogen was Staphylococcus aweus; there was eradication of 15/25 pathogens (60%) with azithromycin and 13/23 (57%) with erythromycin. In study B, 94 and 93 patients were clinically assessed at weeks 1 and 2, respectively: clinical cure was achieved with all treatment regimens at week 1; at week 2 there was reappearance of symptoms in one patient with a mixed infection who had received 3-day azithromycin. Bacteriological eradication was achieved with 1-day and 3-day azithromycin in all patients at weeks 1 and 2; with doxycycline, eradication was achieved in all patients with gonococcal and mixed infections, and in 13/14 patients with chlamydial infection. Side effects (gastrointestinal) occurred infivepatients (12.5%) receiving erythromycin, but in none of those on azithromycin or doxycycline. No clinically significant laboratory abnormalities were attributed to any study treatment. These studies suggest that azithromycin is as effective as erythromycin in the treatment of skin and soft-tissue infections, and that in sexually transmitted gonococcal and chlamydial infections single-dose azithromycin is as effective as 7-day doxycycline therapy. The successful single-dose treatment of genitourinary chlamydial infections may make azithromycin a significant advance in the treatment of this condition.
Introduction Azithromycin (CP-62,993) is a new antibiotic and the prototype of a new class, the azalides. It has been shown to possess unusual pharmacokinetic properties in producing high and sustained tissue concentrations (Girard et al., 1987). Macrophage uptake and debvery to the site of infection is thought to play a role in the distribution of this antibiotic (Gladue et al., 1989). In-vitro studies have demonstrated that this compound is active against a wide range of bacteria. For example, amongst skin and soft-tissue pathogens, azithromycin and 115 0305-7453/90/25A115+07 $02.00/0
© 1990 The British Society for Antimicrobial Chemotherapy
Downloaded from http://jac.oxfordjournals.org/ at University of California, San Francisco on December 9, 2014
A. Lassos
116
A. Lassos
Materials and methods
Antibiotics Azithromycin was obtained from Pfizer Central Research, Sandwich, UK. Comparative agents were erythromycin stearate (Abbott Laboratories, Finland) in the study of skin and soft-tissue infections and doxycycline (Pfizer Central Research) for the sexually transmitted disease (STD) study. Protocol A: skin and soft-tissue infections A total of 82 patients were enrolled in the study. Demographic details are given in Table I. The criterion for inclusion was the presence of acute bacterial infection of the skin or soft tissue (see Table II). The main exclusion criteria were serious illness, antibiotic therapy immediately preceding the start of the study, and known sensitivity
Tabk L Characteristics of patients enrolled in both studies
Skin and soft-tissue study Total (M/F) Age (years) mean range STD study Total (M/F) Age (years) mean range
1-day*
Azithromycin 3-day
5-day
Erythromycin
Doxycycline
—
—
23/19
23/17
—
— —
— —
44-9 18-77
43-8 18-68
— —
22/16
23/11
—
—
19/17
28-5 18-47
281 18-53
— —
— —
30-1 18-50
•Singk-dose. All patients were of Caucasian race.
Downloaded from http://jac.oxfordjournals.org/ at University of California, San Francisco on December 9, 2014
erythromycin have been shown to be equally active (in terms of MIC*,) against Staphylococcus aureus (both methicillin-resistant and -susceptible strains) and S. epidermidis (Hardy et al., 1988). Amongst sexually transmitted pathogens, azithromycin shows good activity against Neisseria gonorrhoeae, with an MIQo of 0-06 mg/1, the lowest value for the ten macrolidcs compared in one particular study (Hardy et al., 1988). For ten strains of Chlamydia trachomatis, MIC ranges have been found to be 0-064-0-25, 0-064-0-128 and 0016-0064 mg/1 for azithromycin, erythromycin and doxycycline, respectively (Scieux et al., 1990, this Volume). The pharmacological features and in-vitro activity suggest not only that azithromycin may be clinically useful in a number of human infections but also that a once-daily dosage regimen or even single-dose therapy may be successful. Early data support this view in the case of sexually transmitted diseases (Steingrimsson et al, 1990, this Volume). This present paper concerns two open, randomized, comparative studies with azithromycin, one in skin and soft-tissue infections and the other in sexually transmitted diseases (STD), carried out in Finland. The aim in both studies was to assess the clinical efficacy of azithromycin and to compare it with that of standard treatment.
Skin and loft-tissae infections and STD
117
TaMe II. Clinical diagnoses in the skin and soft-tissue study Diagnosis
Number of patients azithromycin erythromycin 28 9 3 1 1
30 4 2 3 1
Total
42
40
to macrolides. Informed consent was obtained in all cases and the study was approved by the ethics committee of the Helsinki University Central Hospital. Every patient underwent a full clinical examination before the start of therapy. In this study, patients were enrolled on the basis of clinical diagnosis alone, although every attempt was made to isolate causative pathogens from swabs or pus. Treatment was allowed to start before the results of bacteriological investigation were known. MIC determinations were made with azithromycin against all pathogens, by dilution in Mueller-Hinton agar with 1 % isovitalex and 6% heated horse blood, and an inoculum of approximately lO^cfu/spot, incubated for 48 h at 35°C. Patients were assigned according to a pre-determined randomization list to one of two treatment groups: group 1, azithromycin 2 x 2 5 0 m g given 12 h apart on day 1 followed by 250 mg/day on days 2-5; group 2, erythromycin stearate 500 mg every 6 h for seven days. Assessment of efficacy (clinical and bacteriological), tolerance and safety was made within 0-48 h and 7-10 days after the end of treatment Laboratory safety parameters were additionally assessed one month after the end of treatment. Protocol B: sexually transmitted disease (STD) A total of 108 patients were enrolled in the study. Demographic details are given in Table I. The criteria for inclusion were clinical signs and symptoms of urethritis and/or cervicitis, and bacteriological evidence of infection with N. gonorrhoeae and/or C. trachomatis. The main exclusion criteria were antibiotic therapy immediately preceding the start of the study and known hypersensitivity to macrolide or tetracycline antibiotics. Informed consent was obtained in all cases and the study was approved by the ethics committee of the Helsinki University Central Hospital. All patients underwent a full physical examination before treatment. All patients were screened for causative pathogens and preselected on this basis before entry into the study. Pre-treatment urethral/cervical swabs were taken for Gram staining and gonococcal and chlamydial culture, and for the fluorescein conjugated antibody test for antigen; anorectal and pharyngeal swabs were cultured for N. gonorrhoeae if indicated. Only cases confirmed culturally (N. gonorrhoeae) or by means of a positive antigen test (C. trachomatis) were evaluated for efficacy. MIC determinations were made for azithromycin against both pathogens and for doxycycline against N. gonorrhoeae. MICs for chlamydia isolates were determined by the method of Bowie, Lee & Alexander (1978). Patients were assigned according to a pre-determined randomization list to one of the following three treatment groups: group 1, azithromycin single 1 g dose
Downloaded from http://jac.oxfordjournals.org/ at University of California, San Francisco on December 9, 2014
Pyoderma Abscess, funinculosis, etc. Infected wound, ulcer or dermatitis Erysipelas Other
118 Table HI. Clinical response in the skin and soft-tissue study, assessed 7-10 days after treatment Azithromycin 42 35
40 33 25 2 6
29 1 5 7
6 2 0
0 2*
5*
5
Treatment stopped became of side effects; *S. aureus and S. epidermidis with azithromycin MICs 4-8 mg/1.
(4 x 250 mg); group 2, azithromycin 500 mg (2 x 250 mg) single dose on day 1 followed by 250 mg/day on days 2 and 3; group 3, doxycycline 100 mg every 12 h for seven days. Assessment of efficacy (clinical and bacteriological), toleration and safety was carried out at one and two weeks after the start of therapy. In addition, side effects and laboratory safety parameters were assessed four weeks after the start of therapy. Bacteriological efficacy was assessed only in those patients evaluated for clinical response. Laboratory safety tests All patients underwent laboratory evaluation consisting of haematology (haemoglobin, mean corpuscular volume, red and white cell counts and differential, platelet count, and prothrombin time); blood biochemistry (aspartate aminotransferase, alanine aminotransferase, creatinine phosphokinase, y-glutamyl transaminase, alkaline phosphatase, bilirubin, blood urea, creatinine, total protein, albumin, cholesterol, blood glucose, sodium, potassium, bicarbonate and chloride); and urine analysis (protein, blood and glucose, with microscopy if dipstick tests indicated any abnormality). Table IV. Bacteriological response in the skin and soft-tissue study—eradication of initial pathogens as assessed 7-10 days after the end of treatment Baseline pathogens Staphylococci Streptococci Others
Bacteriological eradication* azithromycin erythromycin 11/20 2/3 2/2
7/15 2/2 4/6
15/25 (60%)
13/23 (57%)
•Number of isolates eradicated/number of isolates. Resistant organisms were excluded from evaluation.
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No. of patients enrolled No. of patients evaluable cured improved failed No. of patients not evaluable lost to follow-up inadequate course ( < 3 days) resistant bacteria
Erythromycin
Skin and soft-tissue Infections and STD
119
Definitions In the skin and soft-tissue infection study, clinical 'cure' was defined as resolution of symptoms with not more than a slight erythema remaining. 'Improvement' was an incomplete resolution of symptoms but with an absence of pus and a decrease in inflammation and fever. In the STD study, clinical 'cure' was denned as the disappearance of symptoms and the presence of < 5 leucocytes per high-power field in a urethral smear.
Skin and soft-tissue infection Table II lists the clinical diagnoses. Tables III and IV show the clinical and bacterial responses, respectively, at second follow-up. Of the 69 patients clinically evaluable, 30 of 35 (86%) were clinically cured or improved on azithromycin therapy, compared with 27 of 33 (82%) on erythromycin. Patients with resistant bacteria (S. aureus and S. epidermidis) completed the protocol; no additional antibiotic was required. Bacteriological eradication of strains sensitive to the antibiotic in vitro was achieved in 15 of 25 cases (60%) with azithromycin and in 13 of 23 cases (57%) with erythromycin. The most common initial pathogen was S. aureus. MICs for the bacteria eradicated by azithromycin ranged from 0125 to 2-Omg/l. MICs for the strains not eradicated by azithromycin also ranged from 0-125 to 2-Omg/l: STD The diagnoses of all patients are summarized in Table V. Most infections were of the urethra or cervix, with a few cases of rectal or pharyngeal infection. The clinical response has been analysed according to pathogen (Table VI). All evaluable cases were cured, except for one mixed-pathogen urethral infection in the 3-day azithromycin group; as eradication of the initial pathogens was achieved, re-infection with another pathogen such as ureaplasma may have occurred. Bacteriological eradication (Table VII) was achieved in all evaluable cases except for one instance of chlamydial infection in the doxycycline group. This case, although clinically cured, was probably a treatment failure. Azithromycin eradicated pathogens with MICs ranging from OK) 15 to 0-25 mg/1 for N.gonorrhoeae and 0-05-2-0 mg/1 for Table V. Diagnosis of 108 patients with STD, showing the numbers infected with N. gonorrhoea* (NG) or C. trachomatis (CT) or both (NG + CT) Site of infection Urethra Cervix Rectum Pharynx No. of patients'
Azithromycin single-dose NG CT NG + CT 17 6 1
8 7
3 2 1
20
15
5
Azithromycin 3-day NG CT NG + CT 15 2 2 2 17
5 6 1
6 3 1
11
7
NG 14 5 1 1 14
Doxycycline CT NG + CT 9 5
8 6 1
14
9
"Some patients were infected at more than one site, and some had single infection at one site and mixed infection at another. Some patients were not evaluated at week 1 and/or week 2.
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Results
120
A. Lassos
Table VI. Clinical cure with the three treatment regimens in patients infected with N. gonorrhoeae, C. trachomatis, or both organisms (number of patients cured/number evaluated) Infection
carriers Non-attenders Total
14/14 13/13
15/15 12/12
5/5
5/5
3 2
3 2
37*
37
Azithromycin 3-day week 1 week 2
12/12 11/11
12/12 11/11
9/9
9/9
3 2
4 0
4 0
34
36
36
16/16
14/14
9/9 6/6
9/9 5/6
3 0 34
Doxycycline week 1 week 2
"One patient who received single-dose azithromyrin withdrew from the investigation.
C. trachomatis. Doxycycline was successful against N. gonorrhoeae strains with MICs of 0-25-1 -Omg/1. Five rectal and two pharyngeal infections by one or both pathogen were cured both clinically and bacteriologically by azithromycin, including two cases treated with a single dose. Safety No side effects were reported by patients receiving azithromycin in either study or by those on doxycycline. Five patients on erythromycin reported severe gastrointestinal side effects and withdrew from the trial. No clinically significant laboratory abnormalities were attributed to any of the study treatments. Discussion In both studies azithromycin had an advantage over the comparative agent in terms of frequency of dosage, but the most significant finding was the efficacy of a single dose in genitourinary chlamydial infection. Although effective single-dose therapy for gonorrhoea is already available, azithromycin has three potential advantages for the treatment of urethritis/cervicitis. Firstly, it provides appropriate treatment when the cause of the urethritis/cervicitis is uncertain, and when immediate therapy is required before the
Table VIL Bacteriological eradication* with the three treatment regimens (number of patients in whom pathogen(s) eradicated/number of cases evaluated) Infection N. gonorrhoeae C. trachomatis Mixed infection
Azithromycin single-dose week 1 week 2 14/14 13/13
15/15 12/12
5/5
5/5
'Assessed only in clinically evaluated patients.
Azithromycin 3-day week 1 week 2 16/16
14/14
9/9 6/6
9/9 6/6
Doxycycline week 1 week 2 12/12 10/11
12/12 11/11
9/9
9/9
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N. gonorrhoeae C. trachomatis Mixed infection Not evaluable: Asymptomatic
Azithromycin single-dose week 1 week 2
Skin and soft-tissue infections and STD
121
results of bacteriological or serological tests are available. Secondly, mixed gonorrhoea/ chlamydial infection can be treated with a single agent. Finally, its use for gonorrhoea may prevent post-gonococcal urethritis caused by C. trachomatis. A single-dose regimen is clearly an advantage in terms of compliance with therapy in sexually transmitted diseases. Azithromycin apparently offers the possiblity of treating patients with proven or suspected chlamydial infection with a single dose before they leave the clinic; a significant advance in the treatment of this infection.
Bowie.W. R., Lee, C. K. & Alexander, E. R. (1978). Prediction of efficacy of antimicrobial agents in treatment of infections due to Chlamydia trachomatis. Journal of Infectious Diseases 138, 655-9. Girard, A. E., Girard, D., English, A. R., Gootz, T. D., Cimochowski, C. R., Faiella J. A. et al. (1987). Pharmacokinctic and in vivo studies with azithromycin (CP-62,993), a new macrolide with an extended half-life and excellent tissue distribution. Antimicrobial Agents and Chemotherapy 31, 1948-54. Gladue, R. P., Bright, G. M.p Isaacson, R. E. & Newborg, M. F. (1989). In vitro and in vivo uptake of azithromycin (CP-62,993) by phagocytic cells: possible mechanism of delivery and release at sites of infection. Antimicrobial Agents and Chemotherapy 33, 277-82. Hardy, D. J., Hensey, D. M., Beyer, J. M., Vojtko, C , McDonald, E. J. & Fernandes, P. B. (1988). Comparative in vitro activities of new 14-, 15-, and 16-membered macrolides. Antimicrobial Agents and Chemotherapy 32, 1710-9. Scieux, C, Bianchi, A., Chappey, B., Vassias, I. & Perol, Y. (190). In-vitro activity of azithromycin against Chlamydia trachomatis. Journal of Antimicrobial Chemotherapy 25, Suppl.A, 7-10. Steingrimsson, O., Olafsson, J. H., Thorarinsson, H., Ryan, R. W., Johnson, R. B. & Tilton, R. C. (1990). Azithromycin the treatment of sexually transmitted disease. Journal of Antimicrobial Chemotherapy 25, Suppl. A, 109-14.
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References
Comparative studies of azitfaromydn in skin and soft-tissue infections and sexually transmitted infections by Neisseria and Chlamydia species
Hebinki University Central Hospital, Snellmaninkatu 14. 00170 Helsinki, Finland Two open, randomized, single centre studies have investigated the efficacy and safety of azithromycin (CP-62,993) in the treatment of infections by azithromycin-sensitive pathogens: (A) acute bacterial infections of skin or soft tissue (compared with erythromycin; n = 82); and (B) urethritis and/or ccrvicitis caused by Neisseria gonorrhoeae and/or Chlamydia trachomatis (compared with doxycycline; n •»» 108). In study A, azithromycin was administered to 42 patients forfivedays at a dosage of 250 mg bd on day 1 and 250 mg once daily on days 2-5; erythromycin was given to 40 patients for seven days at a dosage of 500 mg every 6 h. In study B, azithromycin was administered either as a single 1 g dose or as a single 500 mg dose on day 1 and 250 mg once daily on days 2 and 3; doxycycline was given at a dose of 100 mg every 12 h for seven days. In study A, 68 patients were clinically assessed: clinical cure or improvement in patients receiving azithromycin or erythromycin was achieved in 86% and 82%, respectively. The principal causative pathogen was Staphylococcus aweus; there was eradication of 15/25 pathogens (60%) with azithromycin and 13/23 (57%) with erythromycin. In study B, 94 and 93 patients were clinically assessed at weeks 1 and 2, respectively: clinical cure was achieved with all treatment regimens at week 1; at week 2 there was reappearance of symptoms in one patient with a mixed infection who had received 3-day azithromycin. Bacteriological eradication was achieved with 1-day and 3-day azithromycin in all patients at weeks 1 and 2; with doxycycline, eradication was achieved in all patients with gonococcal and mixed infections, and in 13/14 patients with chlamydial infection. Side effects (gastrointestinal) occurred infivepatients (12.5%) receiving erythromycin, but in none of those on azithromycin or doxycycline. No clinically significant laboratory abnormalities were attributed to any study treatment. These studies suggest that azithromycin is as effective as erythromycin in the treatment of skin and soft-tissue infections, and that in sexually transmitted gonococcal and chlamydial infections single-dose azithromycin is as effective as 7-day doxycycline therapy. The successful single-dose treatment of genitourinary chlamydial infections may make azithromycin a significant advance in the treatment of this condition.
Introduction Azithromycin (CP-62,993) is a new antibiotic and the prototype of a new class, the azalides. It has been shown to possess unusual pharmacokinetic properties in producing high and sustained tissue concentrations (Girard et al., 1987). Macrophage uptake and debvery to the site of infection is thought to play a role in the distribution of this antibiotic (Gladue et al., 1989). In-vitro studies have demonstrated that this compound is active against a wide range of bacteria. For example, amongst skin and soft-tissue pathogens, azithromycin and 115 0305-7453/90/25A115+07 $02.00/0
© 1990 The British Society for Antimicrobial Chemotherapy
Downloaded from http://jac.oxfordjournals.org/ at University of California, San Francisco on December 9, 2014
A. Lassos
116
A. Lassos
Materials and methods
Antibiotics Azithromycin was obtained from Pfizer Central Research, Sandwich, UK. Comparative agents were erythromycin stearate (Abbott Laboratories, Finland) in the study of skin and soft-tissue infections and doxycycline (Pfizer Central Research) for the sexually transmitted disease (STD) study. Protocol A: skin and soft-tissue infections A total of 82 patients were enrolled in the study. Demographic details are given in Table I. The criterion for inclusion was the presence of acute bacterial infection of the skin or soft tissue (see Table II). The main exclusion criteria were serious illness, antibiotic therapy immediately preceding the start of the study, and known sensitivity
Tabk L Characteristics of patients enrolled in both studies
Skin and soft-tissue study Total (M/F) Age (years) mean range STD study Total (M/F) Age (years) mean range
1-day*
Azithromycin 3-day
5-day
Erythromycin
Doxycycline
—
—
23/19
23/17
—
— —
— —
44-9 18-77
43-8 18-68
— —
22/16
23/11
—
—
19/17
28-5 18-47
281 18-53
— —
— —
30-1 18-50
•Singk-dose. All patients were of Caucasian race.
Downloaded from http://jac.oxfordjournals.org/ at University of California, San Francisco on December 9, 2014
erythromycin have been shown to be equally active (in terms of MIC*,) against Staphylococcus aureus (both methicillin-resistant and -susceptible strains) and S. epidermidis (Hardy et al., 1988). Amongst sexually transmitted pathogens, azithromycin shows good activity against Neisseria gonorrhoeae, with an MIQo of 0-06 mg/1, the lowest value for the ten macrolidcs compared in one particular study (Hardy et al., 1988). For ten strains of Chlamydia trachomatis, MIC ranges have been found to be 0-064-0-25, 0-064-0-128 and 0016-0064 mg/1 for azithromycin, erythromycin and doxycycline, respectively (Scieux et al., 1990, this Volume). The pharmacological features and in-vitro activity suggest not only that azithromycin may be clinically useful in a number of human infections but also that a once-daily dosage regimen or even single-dose therapy may be successful. Early data support this view in the case of sexually transmitted diseases (Steingrimsson et al, 1990, this Volume). This present paper concerns two open, randomized, comparative studies with azithromycin, one in skin and soft-tissue infections and the other in sexually transmitted diseases (STD), carried out in Finland. The aim in both studies was to assess the clinical efficacy of azithromycin and to compare it with that of standard treatment.
Skin and loft-tissae infections and STD
117
TaMe II. Clinical diagnoses in the skin and soft-tissue study Diagnosis
Number of patients azithromycin erythromycin 28 9 3 1 1
30 4 2 3 1
Total
42
40
to macrolides. Informed consent was obtained in all cases and the study was approved by the ethics committee of the Helsinki University Central Hospital. Every patient underwent a full clinical examination before the start of therapy. In this study, patients were enrolled on the basis of clinical diagnosis alone, although every attempt was made to isolate causative pathogens from swabs or pus. Treatment was allowed to start before the results of bacteriological investigation were known. MIC determinations were made with azithromycin against all pathogens, by dilution in Mueller-Hinton agar with 1 % isovitalex and 6% heated horse blood, and an inoculum of approximately lO^cfu/spot, incubated for 48 h at 35°C. Patients were assigned according to a pre-determined randomization list to one of two treatment groups: group 1, azithromycin 2 x 2 5 0 m g given 12 h apart on day 1 followed by 250 mg/day on days 2-5; group 2, erythromycin stearate 500 mg every 6 h for seven days. Assessment of efficacy (clinical and bacteriological), tolerance and safety was made within 0-48 h and 7-10 days after the end of treatment Laboratory safety parameters were additionally assessed one month after the end of treatment. Protocol B: sexually transmitted disease (STD) A total of 108 patients were enrolled in the study. Demographic details are given in Table I. The criteria for inclusion were clinical signs and symptoms of urethritis and/or cervicitis, and bacteriological evidence of infection with N. gonorrhoeae and/or C. trachomatis. The main exclusion criteria were antibiotic therapy immediately preceding the start of the study and known hypersensitivity to macrolide or tetracycline antibiotics. Informed consent was obtained in all cases and the study was approved by the ethics committee of the Helsinki University Central Hospital. All patients underwent a full physical examination before treatment. All patients were screened for causative pathogens and preselected on this basis before entry into the study. Pre-treatment urethral/cervical swabs were taken for Gram staining and gonococcal and chlamydial culture, and for the fluorescein conjugated antibody test for antigen; anorectal and pharyngeal swabs were cultured for N. gonorrhoeae if indicated. Only cases confirmed culturally (N. gonorrhoeae) or by means of a positive antigen test (C. trachomatis) were evaluated for efficacy. MIC determinations were made for azithromycin against both pathogens and for doxycycline against N. gonorrhoeae. MICs for chlamydia isolates were determined by the method of Bowie, Lee & Alexander (1978). Patients were assigned according to a pre-determined randomization list to one of the following three treatment groups: group 1, azithromycin single 1 g dose
Downloaded from http://jac.oxfordjournals.org/ at University of California, San Francisco on December 9, 2014
Pyoderma Abscess, funinculosis, etc. Infected wound, ulcer or dermatitis Erysipelas Other
118 Table HI. Clinical response in the skin and soft-tissue study, assessed 7-10 days after treatment Azithromycin 42 35
40 33 25 2 6
29 1 5 7
6 2 0
0 2*
5*
5
Treatment stopped became of side effects; *S. aureus and S. epidermidis with azithromycin MICs 4-8 mg/1.
(4 x 250 mg); group 2, azithromycin 500 mg (2 x 250 mg) single dose on day 1 followed by 250 mg/day on days 2 and 3; group 3, doxycycline 100 mg every 12 h for seven days. Assessment of efficacy (clinical and bacteriological), toleration and safety was carried out at one and two weeks after the start of therapy. In addition, side effects and laboratory safety parameters were assessed four weeks after the start of therapy. Bacteriological efficacy was assessed only in those patients evaluated for clinical response. Laboratory safety tests All patients underwent laboratory evaluation consisting of haematology (haemoglobin, mean corpuscular volume, red and white cell counts and differential, platelet count, and prothrombin time); blood biochemistry (aspartate aminotransferase, alanine aminotransferase, creatinine phosphokinase, y-glutamyl transaminase, alkaline phosphatase, bilirubin, blood urea, creatinine, total protein, albumin, cholesterol, blood glucose, sodium, potassium, bicarbonate and chloride); and urine analysis (protein, blood and glucose, with microscopy if dipstick tests indicated any abnormality). Table IV. Bacteriological response in the skin and soft-tissue study—eradication of initial pathogens as assessed 7-10 days after the end of treatment Baseline pathogens Staphylococci Streptococci Others
Bacteriological eradication* azithromycin erythromycin 11/20 2/3 2/2
7/15 2/2 4/6
15/25 (60%)
13/23 (57%)
•Number of isolates eradicated/number of isolates. Resistant organisms were excluded from evaluation.
Downloaded from http://jac.oxfordjournals.org/ at University of California, San Francisco on December 9, 2014
No. of patients enrolled No. of patients evaluable cured improved failed No. of patients not evaluable lost to follow-up inadequate course ( < 3 days) resistant bacteria
Erythromycin
Skin and soft-tissue Infections and STD
119
Definitions In the skin and soft-tissue infection study, clinical 'cure' was defined as resolution of symptoms with not more than a slight erythema remaining. 'Improvement' was an incomplete resolution of symptoms but with an absence of pus and a decrease in inflammation and fever. In the STD study, clinical 'cure' was denned as the disappearance of symptoms and the presence of < 5 leucocytes per high-power field in a urethral smear.
Skin and soft-tissue infection Table II lists the clinical diagnoses. Tables III and IV show the clinical and bacterial responses, respectively, at second follow-up. Of the 69 patients clinically evaluable, 30 of 35 (86%) were clinically cured or improved on azithromycin therapy, compared with 27 of 33 (82%) on erythromycin. Patients with resistant bacteria (S. aureus and S. epidermidis) completed the protocol; no additional antibiotic was required. Bacteriological eradication of strains sensitive to the antibiotic in vitro was achieved in 15 of 25 cases (60%) with azithromycin and in 13 of 23 cases (57%) with erythromycin. The most common initial pathogen was S. aureus. MICs for the bacteria eradicated by azithromycin ranged from 0125 to 2-Omg/l. MICs for the strains not eradicated by azithromycin also ranged from 0-125 to 2-Omg/l: STD The diagnoses of all patients are summarized in Table V. Most infections were of the urethra or cervix, with a few cases of rectal or pharyngeal infection. The clinical response has been analysed according to pathogen (Table VI). All evaluable cases were cured, except for one mixed-pathogen urethral infection in the 3-day azithromycin group; as eradication of the initial pathogens was achieved, re-infection with another pathogen such as ureaplasma may have occurred. Bacteriological eradication (Table VII) was achieved in all evaluable cases except for one instance of chlamydial infection in the doxycycline group. This case, although clinically cured, was probably a treatment failure. Azithromycin eradicated pathogens with MICs ranging from OK) 15 to 0-25 mg/1 for N.gonorrhoeae and 0-05-2-0 mg/1 for Table V. Diagnosis of 108 patients with STD, showing the numbers infected with N. gonorrhoea* (NG) or C. trachomatis (CT) or both (NG + CT) Site of infection Urethra Cervix Rectum Pharynx No. of patients'
Azithromycin single-dose NG CT NG + CT 17 6 1
8 7
3 2 1
20
15
5
Azithromycin 3-day NG CT NG + CT 15 2 2 2 17
5 6 1
6 3 1
11
7
NG 14 5 1 1 14
Doxycycline CT NG + CT 9 5
8 6 1
14
9
"Some patients were infected at more than one site, and some had single infection at one site and mixed infection at another. Some patients were not evaluated at week 1 and/or week 2.
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Results
120
A. Lassos
Table VI. Clinical cure with the three treatment regimens in patients infected with N. gonorrhoeae, C. trachomatis, or both organisms (number of patients cured/number evaluated) Infection
carriers Non-attenders Total
14/14 13/13
15/15 12/12
5/5
5/5
3 2
3 2
37*
37
Azithromycin 3-day week 1 week 2
12/12 11/11
12/12 11/11
9/9
9/9
3 2
4 0
4 0
34
36
36
16/16
14/14
9/9 6/6
9/9 5/6
3 0 34
Doxycycline week 1 week 2
"One patient who received single-dose azithromyrin withdrew from the investigation.
C. trachomatis. Doxycycline was successful against N. gonorrhoeae strains with MICs of 0-25-1 -Omg/1. Five rectal and two pharyngeal infections by one or both pathogen were cured both clinically and bacteriologically by azithromycin, including two cases treated with a single dose. Safety No side effects were reported by patients receiving azithromycin in either study or by those on doxycycline. Five patients on erythromycin reported severe gastrointestinal side effects and withdrew from the trial. No clinically significant laboratory abnormalities were attributed to any of the study treatments. Discussion In both studies azithromycin had an advantage over the comparative agent in terms of frequency of dosage, but the most significant finding was the efficacy of a single dose in genitourinary chlamydial infection. Although effective single-dose therapy for gonorrhoea is already available, azithromycin has three potential advantages for the treatment of urethritis/cervicitis. Firstly, it provides appropriate treatment when the cause of the urethritis/cervicitis is uncertain, and when immediate therapy is required before the
Table VIL Bacteriological eradication* with the three treatment regimens (number of patients in whom pathogen(s) eradicated/number of cases evaluated) Infection N. gonorrhoeae C. trachomatis Mixed infection
Azithromycin single-dose week 1 week 2 14/14 13/13
15/15 12/12
5/5
5/5
'Assessed only in clinically evaluated patients.
Azithromycin 3-day week 1 week 2 16/16
14/14
9/9 6/6
9/9 6/6
Doxycycline week 1 week 2 12/12 10/11
12/12 11/11
9/9
9/9
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N. gonorrhoeae C. trachomatis Mixed infection Not evaluable: Asymptomatic
Azithromycin single-dose week 1 week 2
Skin and soft-tissue infections and STD
121
results of bacteriological or serological tests are available. Secondly, mixed gonorrhoea/ chlamydial infection can be treated with a single agent. Finally, its use for gonorrhoea may prevent post-gonococcal urethritis caused by C. trachomatis. A single-dose regimen is clearly an advantage in terms of compliance with therapy in sexually transmitted diseases. Azithromycin apparently offers the possiblity of treating patients with proven or suspected chlamydial infection with a single dose before they leave the clinic; a significant advance in the treatment of this infection.
Bowie.W. R., Lee, C. K. & Alexander, E. R. (1978). Prediction of efficacy of antimicrobial agents in treatment of infections due to Chlamydia trachomatis. Journal of Infectious Diseases 138, 655-9. Girard, A. E., Girard, D., English, A. R., Gootz, T. D., Cimochowski, C. R., Faiella J. A. et al. (1987). Pharmacokinctic and in vivo studies with azithromycin (CP-62,993), a new macrolide with an extended half-life and excellent tissue distribution. Antimicrobial Agents and Chemotherapy 31, 1948-54. Gladue, R. P., Bright, G. M.p Isaacson, R. E. & Newborg, M. F. (1989). In vitro and in vivo uptake of azithromycin (CP-62,993) by phagocytic cells: possible mechanism of delivery and release at sites of infection. Antimicrobial Agents and Chemotherapy 33, 277-82. Hardy, D. J., Hensey, D. M., Beyer, J. M., Vojtko, C , McDonald, E. J. & Fernandes, P. B. (1988). Comparative in vitro activities of new 14-, 15-, and 16-membered macrolides. Antimicrobial Agents and Chemotherapy 32, 1710-9. Scieux, C, Bianchi, A., Chappey, B., Vassias, I. & Perol, Y. (190). In-vitro activity of azithromycin against Chlamydia trachomatis. Journal of Antimicrobial Chemotherapy 25, Suppl.A, 7-10. Steingrimsson, O., Olafsson, J. H., Thorarinsson, H., Ryan, R. W., Johnson, R. B. & Tilton, R. C. (1990). Azithromycin the treatment of sexually transmitted disease. Journal of Antimicrobial Chemotherapy 25, Suppl. A, 109-14.
Downloaded from http://jac.oxfordjournals.org/ at University of California, San Francisco on December 9, 2014
References
